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Background: Microsporum audouinii has resurged recently. Infections with the dermatophyte are difficult to treat, which raises the question if we treat M. audouinii infections with the most effective antifungal (AF) agent. Objectives: The aims of this study was to investigate an outbreak of tinea capitis (TC) in Denmark, address the challenges in outbreak management and to conduct two reviews regarding previous outbreaks and minimal inhibitory concentration (MIC). Methods: We used Wood's light, culture, direct microscopy, and PCR for screening and antifungal susceptibility testing (AFST) for treatment optimization. We performed two reviews to explore M. audouinii outbreaks and MIC values using broth microdilution method. Results: Of 73 screened individuals, 10 had confirmed M. audouinii infections. Clinical resistance to griseofulvin was observed in 4 (66%) cases. While previous outbreaks showed high griseofulvin efficacy, our study favoured terbinafine, fluconazole and itraconazole in our hard‐to‐treat cases. AFST guided the choice of AF. Through the literature search, we identified five M. audouinii outbreaks, where differences in management included the use of Wood's light and prophylactic topical AF therapy. Terbinafine MIC values from the literature ranged from 0.002 to 0.125 mg/L. Conclusion: Use of Wood's light and preventive measurements were important for limiting infection. The literature lacked MIC data for griseofulvin against M. audouinii, but indicated sensitivity for terbinafine. The clinical efficacy for M. audouinii treatment was contradictory favouring both terbinafine and griseofulvin. AFST could have a key role in the treatment of difficult cases, but lack of standardisation of AFST and MIC breakpoints limits its usefulness. [ABSTRACT FROM AUTHOR]

Secukinumab and Dead Sea treatment result in clear skin for many psoriasis patients, through distinct mechanisms. However, recurrence in the same areas after treatments suggests the existence of a molecular scar. We aimed to compare the molecular and genetic differences in psoriasis patients who achieved complete response from secukinumab and Dead Sea climatotherapy treatments. We performed quantitative immunohistochemical and transcriptomic analysis, in addition to digital spatial profiling of skin punch biopsies. Histologically, both treatments resulted in a normalization of the lesional skin to a level resembling nonlesional skin. Interestingly, the transcriptome was not normalized by either treatments. We revealed 479 differentially expressed genes between secukinumab and Dead Sea climatotherapy at the end of treatment, with a psoriasis panel identifying SERPINB4, SERPINB13, IL36G, IL36RN, and AKR1B10 as upregulated in Dead Sea climatotherapy compared with secukinumab. Using digital spatial profiling, pan-RAS was observed to be differentially expressed in the microenvironment surrounding CD103+ cells, and IDO1 was differentially expressed in the dermis when comparing the two treatments. The differences observed between secukinumab and Dead Sea climatotherapy suggest the presence of a molecular scar, which may stem from mechanistically different pathways and potentially contribute to disease recurrence. This may be important for determining treatment response duration and disease memory. [ABSTRACT FROM AUTHOR]

Background: Heat shock protein 90 (HSP90) is an important chaperone supporting the function of many proinflammatory client proteins. Recent studies indicate HSP90 inhibition may be a novel mechanism of action for inflammatory skin diseases; however, this has not been explored in atopic dermatitis (AD). Objectives: Our study aimed to investigate HSP90 as a novel target to treat AD. Methods: Experimental models of AD were used including primary human keratinocytes stimulated with cytokines (TNF/IFNg or TNF/IL-4) and a mouse model established by MC903 applications. Results: In primary human keratinocytes using RT-qPCR, the HSP90 inhibitor RGRN-305 strongly suppressed the gene expression of Th1-(TNF, IL1B, IL6) and Th2-associated (CCL17, CCL22, TSLP) cytokines and chemokines related to AD. We next demonstrated that topical and oral RGRN-305 robustly suppressed MC903-induced AD-like inflammation in mice by reducing clinical signs of dermatitis (oedema and erythema) and immune cell infiltration into the skin (T cells, neutrophils, mast cells). Interestingly, topical RGRN-305 exhibited similar or slightly inferior efficacy but less weight loss compared with topical dexamethasone. Furthermore, RNA sequencing of skin biopsies revealed that RGRN-305 attenuated MC903-induced transcriptome alterations, suppressing genes implicated in inflammation including AD-associated cytokines (Il1b, Il4, Il6, Il13), which was confirmed by RT-qPCR. Lastly, we discovered using Western blot that RGRN-305 disrupted JAK-STAT signaling by suppressing the activity of STAT3 and STAT6 in primary human keratinocytes, which was consistent with enrichment analyses from the mouse model. Conclusion: HSP90 inhibition by RGRN-305 robustly suppressed inflammation in experimental models mimicking AD, proving that HSP90 inhibition may be a novel mechanism of action in treating AD. [ABSTRACT FROM AUTHOR]

Atopic dermatitis is one of the most common inflammatory skin diseases among children and adults. Over the last 5 years, the armamentarium for the treatment of this disease, with both topical and systemic drugs, has increased. Treat-to-target is basically the concept where a treatment goal and a time frame for that goal is set at initiation of a new treatment, and if the goals are not achieved in time, treatment will be adjusted. In clinical trials, treatment targets are based on scoring systems for disease severity as recommended by the Harmonizing Outcome Measure for Eczema (HOME) initiative, with the primary endpoint being a reduction of at least 75% of the baseline Eczema Area and Severity Index (EASI) score (EASI-75). The question, however, is if these are useful targets in real-world settings and how this should be implemented in everyday clinical practice. In rheumatology, setting a measurable target and a time frame for an instigated therapy has been shown to lead to more efficient and successful treatment. For atopic dermatitis, the instruments recommended by HOME form the core outcome measures for the treat-to-target frameworks published to date, which are based on expert consensus and Delphi processes. Although atopic dermatitis patients have a high risk of co-morbidities, including physical, psychological and socioeconomic, instruments to measure the severity of co-morbidities have not been included in these existing frameworks. In order to apply a treat-to-target strategy that is meaningful for both the patient and the doctor, validated tools for the measurement of treatment effect on co-morbidities exist and should be included in a shared decision-making process with the individual patient when choosing which targets to aim for and what should be considered treatment success. An obvious limitation for the implementation of a treat-to-target strategy in the clinical setting with atopic dermatitis is that retrieving the data needed is very time consuming. This could to some degree be mitigated by the use of electronic applications in which patients could report their outcomes. [ABSTRACT FROM AUTHOR]

Hidradenitis suppurativa is a chronic inflammatory skin disease with limited treatment options. The poorly understood pathogenesis hinders the development of effective treatments; therefore, a pressing need exists to further elucidate the molecular mechanisms in hidradenitis suppurativa. This study investigated the underlying inflammatory pathways and cell types in hidradenitis suppurativa using transcriptomic approaches with RNA sequencing of lesional and non-lesional skin biopsies from hidradenitis suppurativa, which was jointly analyzed with previously published transcriptomic data from atopic dermatitis and psoriasis patients. The differential expression and pathway enrichment analyses demonstrated the activation of multiple inflammatory processes, including the innate and adaptive immune systems, implicated in the hidradenitis suppurativa pathogenesis. In agreement, hidradenitis suppurativa exhibited a unique and heterogeneous cell type signature involving lymphoid and myeloid cells such as B cells and macrophages. Furthermore, hidradenitis suppurativa displayed increased expression of TH1/2/17 signatures with no predominant TH signatures unlike psoriasis (TH1/17) and atopic dermatitis (TH2). In summary, our study provides molecular insights into the pathomechanisms in hidradenitis suppurativa, revealing a strong and widespread immune activation, which may benefit from treatment strategies offering a broad immunomodulation of various key inflammatory pathways. Our data not only corroborate previously reported findings but also enhance our understanding of the immune dysregulation in hidradenitis suppurativa, uncovering novel and potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Immune mediated inflammatory diseases (IMIDs) are a heterogeneous group of debilitating, multifactorial and unrelated conditions featured by a dysregulated immune response leading to destructive chronic inflammation. The immune dysregulation can affect various organ systems: gut (e.g., inflammatory bowel disease), joints (e.g., rheumatoid arthritis), skin (e.g., psoriasis, atopic dermatitis), resulting in significant morbidity, reduced quality of life, increased risk for comorbidities, and premature death. As there are no reliable disease progression and therapy response biomarkers currently available, it is very hard to predict how the disease will develop and which treatments will be effective in a given patient. In addition, a considerable proportion of patients do not respond sufficiently to the treatment. ImmUniverse is a large collaborative consortium of 27 partners funded by the Innovative Medicine Initiative (IMI), which is sponsored by the European Union (Horizon 2020) and in-kind contributions of participating pharmaceutical companies within the European Federation of Pharmaceutical Industries and Associations (EFPIA). ImmUniverse aims to advance our understanding of the molecular mechanisms underlying two immune-mediated diseases, ulcerative colitis (UC) and atopic dermatitis (AD), by pursuing an integrative multi-omics approach. As a consequence of the heterogeneity among IMIDs patients, a comprehensive, evidence-based identification of novel biomarkers is necessary to enable appropriate patient stratification that would account for the inter-individual differences in disease severity, drug efficacy, side effects or prognosis. This would guide clinicians in the management of patients and represent a major step towards personalized medicine. ImmUniverse will combine the existing and novel advanced technologies, including multi-omics, to characterize both the tissue microenvironment and blood. This comprehensive, systems biology-oriented approach will allow for identification and validation of tissue and circulating biomarker signatures as well as mechanistic principles, which will provide information about disease severity and future disease progression. This truly makes the ImmUniverse Consortium an unparalleled approach. [ABSTRACT FROM AUTHOR]

Psoriasis is a common chronic inflammatory skin disease accompanied by heterogenous clinical and histological features, including a characteristic keratinocyte hyperproliferation and dermal immunogenic profile. In addition, psoriasis is associated with widespread transcriptomic alterations including changes in microRNA (miRNA) and circular RNA (circRNA) abundance, which constitute non-coding RNA (ncRNA) classes with specific regulatory capacities in diverse physiological and pathological processes. However, the knowledge about the expression dynamics of ncRNA during psoriasis treatment is sparse. To elucidate the dynamics of miRNA and circRNA abundance during secukinumab (anti-IL-17A) treatment, we studied their expression patterns in skin biopsies from 14 patients with severe plaque-type psoriasis before and during an 84-day secukinumab therapy at day 0, 4, 14, 42, and 84 using NanoString nCounter technology. We found a comprehensive downregulation of the majority of investigated circRNAs and specific alterations in the miRNA profile, including an upregulation of miR-203a-3p, miR-93-5p, and miR-378i in lesional compared to non-lesional skin before treatment. During treatment, the circRNAs progressively returned to the expression levels observed in non-lesional skin and already four days after treatment initiation most circRNAs were significantly upregulated. In comparison, for miRNAs, the normalization to baseline during treatment was delayed and limited to a subset of miRNAs. Moreover, we observed a strong correlation between multiple circRNAs, including ciRS-7 and circPTPRA, and the psoriasis area and severity index (PASI). Similar pronounced correlations could, however, not be found for miRNAs. Finally, we did not observe any significant changes in circRNA expression in peripheral blood mononuclear cells during treatment. In conclusion, we uncovered a rapid shift in global circRNA abundance upon anti-IL-17A treatment, which predated clinical and histological improvements, and a strong correlation with PASI, indicating a biomarker potential of individual circRNAs. [ABSTRACT FROM AUTHOR]

Climatotherapy is a well‐described treatment of psoriasis. Dead Sea climatotherapy (DSC) in Israel consists of intensive sun and Dead Sea bathing and is very effective in improving clinical and patient‐reported outcomes. However, the effect of DSC has not been widely studied. We aimed to investigate the effect of DSC on psoriasis skin using quantitative immunohistochemistry techniques and analysis of blood samples. Skin punch biopsies from 18 psoriasis patients from a previous cohort study were used. Biopsies were obtained from non‐lesional skin and from a psoriasis target lesion at baseline. A biopsy was acquired from the target lesion after DSC. Among patients who achieved complete visual clearance, a biopsy was also obtained at relapse. Blood samples were obtained at the same time points. We performed haematoxylin and eosin staining and quantitative immunohistochemical analysis of CD3, CD4, CD8, CD11c, CD103, CD163, CD207, forkhead box P3, Ki67 and myeloperoxidase. We performed blood tests of cholesterol, c‐reactive protein, glucose, haemoglobin A1c and triglycerides. All skin biomarkers except for CD207 were decreased after DSC. At relapse, none of the biomarkers were significantly different from the baseline lesional measurements. Total CD207 staining correlated with psoriasis area and severity index at baseline while CD163 staining correlated with psoriasis area and severity index at EOT. No changes were observed in selected blood tests during the study. Consistent with clinical results, DSC is highly effective in the short term almost normalising all investigated biomarkers. However, at relapse, biomarkers were upregulated to the baseline level. [ABSTRACT FROM AUTHOR]

Immunohistochemical quantification of inflammatory cells in skin biopsies is a valuable tool for diagnosing skin diseases and assessing treatment response. The quantification of individual cells in biopsies is time-consuming, tedious, and difficult. In this study, we presented and compared two methods for the quantification of CD8+ T cells in skin biopsies from patients with psoriasis using both commercial software (Adobe Photoshop) and open-source software (Qupath). In addition, we provided a detailed, step-by-step description of both methods. The methods are scalable by replacing the CD8 antibody with other antibodies to target different cells. Moreover, we investigated the correlation between quantifying CD8+ cells normalized to area or epidermal length and cell classifications, compared cell classifications in QuPath with threshold classifications in Photoshop, and analyzed the impact of data normalization to epidermal length or area on inflammatory cell densities in skin biopsies from patients with psoriasis. We found a satisfactory correlation between normalizing data to epidermal length and area for psoriasis skin. However, when non-lesional and lesional skin samples were compared, a significant underestimation of inflammatory cell density was found when data were normalized to area instead of epidermal length. Finally, Bland–Altman plots comparing Qupath and Photoshop to quantify inflammatory cell density demonstrated a good agreement between the two methods. [ABSTRACT FROM AUTHOR]

Background: Several cancers, including mycosis fungoides (MF), have reported dysregulation of miR‐195‐5p. miR‐195‐5p plays a role in cell cycle regulation in several malignant diseases. Objectives: This study aimed to investigate: (a) the expression level of miR‐195‐5p in lesional MF skin biopsies and (b) the potential regulatory roles of miR‐195‐5p in MF. Methods: Quantitative real‐time polymerase chain reaction (RT‐qPCR) was used to determine miR‐195‐5p expression in MF skin biopsies and cell lines. The effect of miR‐195‐5p and ADP‐ribosylation factor‐like protein 2 (ARL2) on cell cycle and apoptosis was measured by flow cytometry assays. Changes in ARL2 expression were determined by RT‐qPCR and Western blotting (WB). Results: We found lower expression levels of miR‐195‐5p in lesional skin from MF patients compared with non‐lesional MF skin and skin from healthy volunteers. Additionally, miR‐195‐5p showed lower expression levels in the skin from patients with disease progression compared with patients with stable disease. In vitro studies showed that overexpression of miR‐195‐5p induced a cell cycle arrest in G0G1. Using microarray analysis, we identified several genes that were regulated after miR‐195‐5p overexpression. The most downregulated gene after miR‐195‐5p mimic transfection was ARL2. RT‐qPCR and WB analyses confirmed downregulation of ARL2 following transfection with miR‐195‐5p mimic. Lastly, transfection with siRNA against ARL2 also induced a G0G1 arrest. Conclusion: Upregulation of miR‐195‐5p in MF inhibits cycle arrest by downregulation of ARL2. miR‐195‐5p may thus function as a tumor suppressor in MF and low miR‐195‐5p expression in lesional MF skin may promote disease progression. [ABSTRACT FROM AUTHOR]

Keratinocytes are the key cellular target for IL‐17A‐mediated effects in psoriasis and HSP90 is important for IL‐17A‐mediated signalling. RGRN‐305 is a novel HSP90 inhibitor reported to reduce psoriatic phenotypes in preclinical animal models. The aim of this study was to investigate the effect of RGRN‐305 on a psoriasis‐like inflammatory response in human keratinocytes in vitro. Using RT‐qPCR, we demonstrated a significantly increased expression of the HSP90 isoforms HSP90AB1, HSP90B1 and TRAP1 in lesional compared with non‐lesional psoriatic skin. In a psoriasis‐like setting where keratinocytes were stimulated with TNFα and/or IL‐17A, we analysed the mRNA expression using the NanoString nCounter technology and demonstrated that the HSP90 inhibitor RGRN‐305 significantly reduced the IL‐17A‐ and TNFα‐induced gene expression of a number of proinflammatory genes, including the psoriasis‐associated genes CCL20, NFKBIZ, IL36G and IL23A. In agreement with the mRNA data, the protein level of CCL20, IκBζ and IL‐36γ were inhibited by RGRN‐305 as demonstrated by western blotting and ELISA. Interestingly, when keratinocytes were stimulated with a TLR3 agonist, RGRN‐305 also demonstrated potent immunomodulatory effects, significantly inhibiting poly(I:C)‐induced expression of the proinflammatory genes TNFα, IL1B, IL6 and IL23A. Taken together, our data support a role for HSP90 not only in the pathogenesis of psoriasis, but also in broader immune responses. Therefore, HSP90 provides an attractive target for the treatment of psoriasis and other diseases where the innate immune system plays an important role. [ABSTRACT FROM AUTHOR]

Psoriasis is a common chronic inflammatory skin disease associated with several comorbidities and reduced quality of life. In the past decades, highly effective targeted therapies have led to breakthroughs in the management of psoriasis, providing important insights into the pathogenesis. This article reviews the current concepts of the pathophysiological pathways and the recent progress in antipsoriatic therapeutics, highlighting key targets, signaling pathways and clinical effects in psoriasis. [ABSTRACT FROM AUTHOR]

The interleukin (IL)-36 cytokine family plays an essential role in inflammatory processes in the skin and is implicated in the pathogenesis of psoriasis. This study explored the role of IL-36 in psoriasis and investigated the molecular mechanism involved in tumour necrosis factor-α (TNFα)/IL-17A-mediated IL-36 induction. In human keratinocytes IL-36 expression was strongly upregulated by combined TNFα and IL-17A stimulation. Moreover, IκBζ, encoded by NFKBIZ, was identified as a key regulator required for TNFα/IL-17A-induced IL-36γ expression. TNFα/IL-17A-induced IL-36γ expression also involved the nuclear factor κB (NF-κB), p38 mitogen-activated protein kinase and ERK1/2 signalling pathways. Furthermore, a specific NF-κB DNA-binding site in the promoter region of IL36G responsible for the TNFα/IL-17A-induced IL36G gene expression was identified. Finally, in a cohort of patients with psoriasis receiving anti-IL-17A treatment, a positive correlation was found between the expression of NFKBIZ and IL36G. In conclusion, these data reveal a novel crucial regulatory mechanism by which TNFα and IL-17A regulate IL-36γ expression. [ABSTRACT FROM AUTHOR]

The article focuses on manufacturers must overcome unique challenges to produce effective microbe-based therapies at scale. Topics include the human medicine has made tremendous progress in the past century, and the cure widespread infectious diseases with antibiotics and vaccines, address behavioral illnesses with antidepressants, and manage cancer care and other diseases with biologies and gene therapies.

The aim was to examine anti‐tumor necrosis factor α (anti‐TNFα) therapy influence changes on Th17 and Th22 cells in patients with spondyloarthritis (SpA), and its correlation with changes in clinical and magnetic resonance imaging (MRI) activity and chronicity scores. The Th17 and Th22 cells were assessed at baseline, after 12 and 52 weeks of anti‐TNFα therapy by flow cytometry (ClinicalTrials.gov NCT4682724). The percentages of both Th17 and Th22 cells were increased by 70% at baseline compared with healthy controls (both p < 0.01). During treatment, these two subsets increased further to be 170% (Th17) and 123% (Th22) above levels in healthy controls (both p < 0.01). The same subsets decrease their expression of IL‐23R significantly during the observation period (p < 0.05). High levels of Th17 and Th22 cells at baseline were associated with the degree of chronic changes in the sacroiliac joints on MRI and a good clinical response to anti‐TNFα treatment after one year. Plasma levels were not associated with clinical changes. Th17 cells, and Th22 subsets, increased during one year of anti‐TNF‐α therapy in SpA, regardless of their clinical improvement. This supports that both the Th17 and Th22 subsets could be involved in the progression in SpA. [ABSTRACT FROM AUTHOR]

It is difficult to distinguish erythrodermic mycosis fungoides from Sézary syndrome due to their similar clinical and histological features. The main purpose of this study was to investigate whether microRNA expression profiles in lesional skin could discriminate patients with erythrodermic mycosis fungoides from those with Sézary syndrome. A further aim was to assess whether the microRNA expression profiles in erythrodermic mycosis fungoides skin was more comparable to microRNA expression profiles of Sézary syndrome or early-stage mycosis fungoides. RNA was extracted from diagnostic skin biopsies, followed by quantitative reverse transcription polymerase chain reaction analysis of 383 microRNAs. Twenty-seven microRNAs were significantly differentially expressed between erythrodermic mycosis fungoides and Sézary syndrome. Moreover, erythrodermic mycosis fungoides showed microRNA features overlapping with Sézary syndrome and early-stage mycosis fungoides, although hierarchical cluster analysis co-clustered erythrodermic mycosis fungoides with early-stage mycosis fungoides rather than with Sézary syndrome. These findings underscore that erythrodermic mycosis fungoides and Sézary syndrome are different diseases. [ABSTRACT FROM AUTHOR]