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Introduction: Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A, is approved for the treatment of moderate-to-severe plaque psoriasis. Since scalp psoriasis can be burdensome and challenging to treat with non-systemic therapies, this post hoc analysis focused on scalp psoriasis in patients with moderate-to-severe plaque psoriasis and baseline scalp involvement. The analysis considered a holistic concept of clearance through 5 years of ixekizumab treatment. Methods: Ixekizumab-treated patients with baseline scalp involvement were pooled from three multicenter, randomized, double-blind, placebo-controlled, phase 3 trials (integrated UNCOVER-1/2 and UNCOVER-3). Analyses were performed on a subpopulation of patients who achieved complete resolution of scalp psoriasis at Week 60 (i.e., Week 60 Psoriasis Scalp Severity Index [PSSI-0] responders) and on the overall patient population (i.e., Week 60 PSSI-0 responders and non-responders), which was used as a reference. Clinical outcomes (PSSI), patient-reported outcomes (Itch Numeric Rating Scale [NRS] score, Skin Pain Visual Analogue Scale [VAS]), quality of life (Dermatology Life Quality Index [DLQI]), and concurrent outcomes were assessed from baseline through 5 years. Descriptive statistics of observed data were reported. Results: After 60 weeks of ixekizumab treatment, 88.4% (UNCOVER-1/2) and 75.9% (UNCOVER-3) of patients with baseline scalp involvement achieved complete clearance (PSSI-0) of scalp psoriasis. Substantial improvements in the clinical outcomes (PSSI), patient-reported outcomes (Itch NRS, Skin Pain VAS), and quality of life (DLQI) were achieved by Week 60 and sustained through Week 264 in the Week 60 PSSI-0 responders and in the overall patient population. Additionally, a significant proportion of Week 60 PSSI-0 responders achieved concurrent complete scalp and skin clearance and quality of life improvement through 5 years. Conclusions: Continued treatment with ixekizumab provided long-term sustained scalp clearance over 5 years to patients with moderate-to-severe plaque psoriasis and baseline scalp involvement, and holistic improvements occurred across clinical outcomes, patient-reported outcomes, and quality of life. Clinical Trial Numbers: NCT01474512 (UNCOVER-1), NCT01597245 (UNCOVER-2), and NCT01646177 (UNCOVER-3). [ABSTRACT FROM AUTHOR]

Introduction: Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A, is an approved treatment for plaque psoriasis. This study aimed to use animated visualizations as a tool to simplify complex data from ixekizumab clinical trials. Methods: Animated visualizations were developed to show outcomes from ixekizumab clinical trials and a Bayesian network meta-analysis of 11 approved biologics. The visualizations simultaneously highlighted both aggregate scores and the individual progression of patients over the course of treatment. Results: The animations provided key messages and information from the complex data in efficient and scientific ways that were also visually pleasing and simple to understand. The animations highlighted (1) rapid reduction in disease severity from baseline; (2) sustained efficacy of ixekizumab in the treatment of skin and nail psoriasis; (3) side-by-side comparisons of treatment efficacy and clinical improvement across trials; (4) simultaneous visual presentation of individual results with summary response over time; and (5) indirect comparison of relative treatment effects with other biologics based on Bayesian network meta-analysis. Conclusion: The rapid and sustained efficacy of ixekizumab in the treatment of psoriasis was demonstrated using multiple dynamic visualizations with different clinical endpoints. Animated visualizations provided a simpler and more comprehensive understanding of complex data than conventional static figures. [ABSTRACT FROM AUTHOR]

Background/Aims: T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon, aggressive malignancy that rarely presents in the skin and is generally not considered as part of the differential diagnosis by dermatologists and dermatopathologists. We describe an unusual case of T-ALL presenting with folliculocentric, erythematous papules on the face, histologically resembling mycosis fungoides (MF). Immunostaining for terminal deoxynucleotidyl transferase (TdT) was positive in tumor cells, supporting the diagnosis of cutaneous involvement by T-ALL. TdT is a nuclear enzyme expressed by immature lymphoid malignancies, but the expression pattern of this marker is not well characterized in the skin. We aimed to assess TdT staining in skin biopsies with similar-appearing lymphocytic infiltrates. Methods: We evaluated the immunostaining profile of TdT in a cohort of 23 patients, including 13 cases of MF and 10 cases of spongiotic dermatitis. Results: The lymphocytes in the MF and spongiotic dermatitis cases lacked nuclear staining for TdT. Nonspecific, granular, cytoplasmic staining was observed in a small number of background cells. Conclusions: TdT may assist dermatopathologists in discriminating malignant infiltrates of T-ALL from other conditions. [ABSTRACT FROM AUTHOR]

Psoriasis vulgaris is a common, heterogeneous, chronic inflammatory skin disease characterized by thickened, red, scaly plaques and systemic inflammation. Psoriasis is also associated with multiple comorbid conditions, such as joint destruction, cardiovascular disease, stroke, hypertension, metabolic syndrome, and chronic kidney disease. The discovery of IL-17--producing T cells in a mouse model of autoimmunity transformed our under- standing of inflammation driven by T lymphocytes and associations with human inflammatory diseases, such as psoriasis. Under the regulation of IL-23, T cells that produce high levels of IL-17 create a self-amplifying, feed-forward inflammatory response in keratinocytes that drives the development of thickened skin lesions infiltrated with a mixture of inflammatory cell populations. Recently, the Food and Drug Administration approved multiple highly effective psoriasis therapies that disrupt IL-17 (secukinumab, ixekizumab, and brodalumab) and IL-23 (guselkumab and tildrakizumab) signaling in the skin, thus leading to a major paradigm shift in the way that psoriatic disease is managed. [ABSTRACT FROM AUTHOR]

Chronic eczematous eruptions of aging (CEEA) refers to a heterogenous group of longstanding, pruritic eczematous dermatoses with an unidentified etiology, or those which do not meet strict disease criteria. The literature has not yet established a single ubiquitous disease or term for these eruptions in adults over the age of 65 years. Instead, CEEA is attributed various names, including immunologic eruption of aging, and eruption of immunosenescence. Atopic dermatitis in the elderly, eczema in the elderly, and late- or adult-onset atopic dermatitis or eczema likely also fall under the umbrella of CEEA, given that older patients often do not meet strict criteria for atopic dermatitis. As a reflection of such terminological heterogeneity, CEEA does not have a standardized workup algorithm. This lack of uniformity can obscure the ability to study and understand appropriate treatments for this condition. Yet, as providers become increasingly aware of CEEA and more comfortable in making this diagnosis in older adults, it is necessary that dermatologists understand the safety and efficacy of common CEEA treatments in this population. Here, we discuss special considerations, challenges, and recommendations for treating older adults with CEEA with topical and systemic therapeutics. We provide an overview of therapeutic strategies and potential barriers to treatment and discuss the essential role of shared decision making when caring for this patient population. [ABSTRACT FROM AUTHOR]

Summary: Background: Oculocutaneous albinism type 2 (OCA2) is caused by mutations of the OCA2 gene. Individuals affected by OCA2 as well as other types of albinism are at a significantly increased risk for sun-induced skin-cancers, including malignant melanoma (MM). Objective: To identify the molecular etiology of oculocutaneous albinism in a previously uncharacterized melanoma pedigree and to investigate the relationship between two OCA2 variants and melanoma predisposition in this pedigree. Methods: DNA and RNA were isolated from the peripheral blood of seven patients in a familial melanoma pedigree. Electron microscopy was performed on the individual with clinical oculocutaneous albinism. OCA2, TYRP1, MC1R, CDKN2A/p16, CDKN2A/p19ARF, and CDK4 genes were sequenced in affected individuals. The relationship between OCA2 variants and melanoma was assessed using a pedigree likelihood-based method. Results: The proband was determined to be an OCA2 compound heterozygous mutation carrier with a previously reported conservative missense mutation (V443I) and a novel non-conservative missense mutation (L734R). The pedigree contained individuals diagnosed with both cutaneous and iris melanoma. Based on co-segregation analysis, the odds of these OCA2 variants being high penetrance loci for melanoma was: 1.3-to-1 if we include the iris melanoma as affected and 6.5-to-1 if we only consider cutaneous melanoma as affected. Conclusion: The discovery of this novel OCA2 variant adds to the body of evidence on the detrimental effects of OCA2 gene mutations on pigmentation, supports existing GWAS data on the relevance of the OCA2 gene in melanoma predisposition, and may ultimately assist in the development of targeted molecular therapies in the treatment of OCA and melanoma. [ABSTRACT FROM AUTHOR]

Psoriasis is a common immune-mediated disease that affects 2%-4% of individuals in North America and Europe. In the past decade, advances in research have led to an improved understanding of immune pathways involved in the pathogenesis of psoriasis and has spurred the development of targeted therapeutics. Recently, three psoriasis autoantigens have been described: cathelicidin ( LL37), a disintegrin and metalloprotease domain containing thrombospondin type 1 motif-like 5 ( ADAMTSL5), and lipid antigens generated by phospholipase A2 ( PLA2) group IVD ( PLA2G4D). It is important to establish the expression, regulation and therapeutic modulation of these psoriasis autoantigens. In this study, we performed immunohistochemistry and two-colour immunofluorescence on non-lesional and lesional psoriasis skin to characterize ADAMTSL5 and LL37, and their co-expression with T cells, dendritic cells, neutrophils and macrophages, which are the main immune cells that drive this disease. Our results showed that ADAMTSL5 and LL37 are significantly ( P<.05) increased in lesional skin and are co-expressed by many dendritic cells, macrophages and some T cells in the dermis. Gene expression analysis showed significant ( P<.05) upregulation of LL37 in lesional skin and significant downregulation following treatment with etanercept. ADAMTSL5 and LL37 are also significantly decreased by IL-17 or TNF-α blockade, suggesting feed-forward induction of psoriasis autoantigens by disease-related cytokines. [ABSTRACT FROM AUTHOR]

Summary: Background: Although alopecia areata (AA) greatly impacts patients' quality of life (QoL), there is no adequate validation of AA‐targeted QoL surveys in clinical trials, hindering sufficient representation of patient‐reported outcomes. Objectives: Better understanding of patient‐reported outcomes may guide treatment goals and future clinical trials. Methods: In a recent randomized controlled trial testing dupilumab in AA, patients were administered the Alopecia Areata Quality of Life Index (AA‐QLI) and the Alopecia Areata Symptom Impact Scale (AASIS) surveys, specifically evaluating QoL in patients with AA. An in‐depth analysis was performed to assess the utility of these questionnaires in this patient population, both at baseline and after treatment, and to determine a threshold for improved patient‐reported outcomes. Results: While AASIS correlated with baseline Severity of Alopecia Tool (SALT) scores and with therapeutic response, AA‐QLI showed no correlation with AA severity before or after treatment. Itch strongly correlated with serum IgE levels across both surveys. Using various approaches to estimate a discriminative threshold for decreased impact of AA on QoL (by AASIS) following treatment, a SALT score of 20 points or less post‐treatment was associated with improved patient‐reported outcomes, including both AA‐related symptoms and items within the daily activities/feelings domain such as 'feeling sad' and 'feeling anxious or worry'. Conclusions: AASIS is better than AA‐QLI to assess patient‐reported outcomes. SALT ≤ 20 following treatment should be considered as a threshold for meaningful therapeutic outcome and as a clinical endpoint in future clinical trials for AA. What is already known about this topic?Alopecia areata greatly compromises quality of life, and affected patients have increased prevalences of depression, anxiety and social phobia.Despite the significant negative impact of the disease on patients' wellbeing, validation of targeted questionnaires in alopecia areata is lacking, and a therapeutic response threshold for improved patient‐reported outcomes is unknown. What does this study add?This study investigated the utility of two different alopecia areata‐targeted questionnaires – Alopecia Areata Quality of Life Index and Alopecia Areata Symptom Impact Scale (AASIS) – in a clinical trial setting.AASIS was found to correlate strongly with alopecia areata severity and clinical response. What are the clinical implications of this work?Patients with ≤ 20% scalp hair loss after treatment reported improvement in multiple quality‐of‐life items, suggesting this as a meaningful therapeutic outcome that may guide clinicians and improve the development of future clinical trials. [ABSTRACT FROM AUTHOR]

Background: Treatments for alopecia areata (AA) patients with extensive scalp hair loss are limited, and recent evidence supports a role for type 2 T‐cell (Th2)‐immune response in AA. Dupilumab, a monoclonal antibody inhibiting Th2 signaling, approved for type 2 diseases including atopic dermatitis, was evaluated in AA patients. Methods: Alopecia areata patients with and without concomitant atopic dermatitis were randomized 2:1 to receive weekly subcutaneous dupilumab (300 mg) or placebo for 24 weeks, followed by another 24‐week dupilumab open‐label phase. The primary outcome was change from baseline in the Severity of Alopecia Tool (SALT) score at week 24; secondary outcomes included a range of measures of hair regrowth. Results: Forty and 20 patients were assigned to the dupilumab and placebo arms, respectively. At week 24, disease worsening was documented in the placebo arm, with a least‐squares mean change in the SALT score of −6.5 (95% confidence‐interval [CI], −10.4 to −2.6), versus a change of 2.2 (95% CI, −0.6 to 4.94) in the dupilumab arm (p <.05). After 48 weeks of dupilumab treatment, 32.5%, 22.5% and 15% of patients achieved SALT30/SALT50/SALT75 improvement, respectively, while in patients with baseline IgE ≥ 200 IU/ml response rates increased to 53.8%, 46.2%, and 38.5%, respectively. Moreover, baseline IgE predicts treatment response with 83% accuracy. No new safety signals were detected. Conclusions: This hypothesis‐driven trial is the first to indicate the possible pathogenic role of the Th2 axis and Th2 targeting in AA patients. Patient selection based on baseline serum IgE levels may improve treatment results (Clinicaltrials.gov number, NCT03359356). [ABSTRACT FROM AUTHOR]

The microRNA-34 family (miR-34a, -34b and -34c) have been reported to be tumor suppressor microRNAs (miRNAs) that are regulated by the TP53 and DNA hypermethylation. However, the expression, regulation, and prognostic value of the miR-34 family have not been systematically studied in colon cancer. To elucidate the roles of miR-34 family in colon carcinogenesis, miR-34a/b/c were measured in tumors and adjacent noncancerous tissues from 159 American and 113 Chinese colon cancer patients using quantitative RT-PCR, and we examined associations between miR-34a/b/c expression with TNM staging, cancer-specific mortality, TP53 mutation status and Affymetrix microarray data. All miR-34 family members were significantly increased in colon tumors, counter to the proposed tumor suppressor role for these miRNAs. Increased miR-34b/c were observed in more advanced tumors in two independent cohorts and increased expression of miR-34b/c was associated with poor cancer-specific mortality. While the expression of miR-34 family was not associated with TP53 mutation status, TP53 transcriptional activity was associated with miR-34a/b/c expression that is consistent with the proposed regulation of miR-34a/b/c by TP53. To examine where the miR-34 family is expressed, the expression of miR-34 family was compared between epitheliums and stromal tissues using laser microdissection technique. The expression of miR-34b/c was increased significantly in stromal tissues, especially in cancer stroma, compared with epithelial tissue. In conclusion, increased miR-34b/c predominantly expressed in stromal tissues is associated with poor prognosis in colon cancer. MiR-34 may contribute to cancer-stromal interaction associated with colon cancer progression. [ABSTRACT FROM AUTHOR]

Psoriasis, psoriatic arthritis, and axial spondyloarthritis are systemic inflammatory diseases, each commonly manifesting as a spectrum of symptoms, complications, and comorbidities that arise differently in individual patients. Drugs targeting inflammatory cytokines common to the pathogenesis of each of these conditions have been developed, although their specific actions in the different tissues involved are variable. For a drug to be effective, it must be efficiently delivered to and locally bioactive in disease-relevant tissues. Detailed clinical data shed light on the therapeutic effects of individual biologics on specific domains or clinical manifestations of disease and assist in guiding treatment decisions. Pharmacologic, molecular, and functional properties of drugs strongly impact their observed safety and efficacy, and an understanding of these properties provides complementary insight. Secukinumab, a fully human monoclonal IgG1/κ antibody selectively targeting interleukin (IL)-17A, has been in clinical use for >6 years in the treatment of moderate to severe psoriasis, psoriatic arthritis, and both radiographic (also known as ankylosing spondylitis) and nonradiographic axial spondyloarthritis. In this review, we discuss pharmacokinetic and pharmacodynamic data for secukinumab to introduce clinicians to the pharmacological properties of this widely used drug. Understanding how these properties affect the observed clinical efficacy, safety, and tolerability of this drug in the treatment of IL-17A–mediated systemic inflammatory diseases is important for all physicians treating these conditions. [ABSTRACT FROM AUTHOR]

Abstract: A simple device for field sampling and concentration of analytes for subsequent introduction into an injection port for gas chromatographic (GC) analysis has been developed. It consists of a tiny, coiled platinum wire filament (CWF) that is attached to a retractable plunger wire, which fits inside a syringe needle housing. Sampling is accomplished by dipping the end of the CWF in a liquid sample, which is drawn into the wire coil by capillary action, and introducing it into the injection port either before or after allowing the solvent to evaporate. The CWF can be used with or without a nonvolatile chemical coating. A major advantage of this sampling device is that nonvolatile sample matrix components remain on the wire coil, reducing the required injection port and liner cleaning frequency and contamination of the head of the chromatographic column. The coil itself can be easily cleaned between analyses by rinsing and/or burning off residual material in a small flame. The sampling coil facilitates specifically designed chemical reactions in the injection port, such as thermochemolysis and methylation. Applications demonstrated in this work include: (1) direct introduction of samples with little or no pre-treatment, (2) simultaneous thermochemolysis and methylation of lipid-containing samples such as bacteria and bacterial endospores for analysis of biomarkers, and (3) solid phase micro-extraction (SPME) using temporary wire coatings. The CWF allowed for significant reduction in sample preparation time, in most cases to less than a few minutes. The peak shapes examined for polycyclic aromatic hydrocarbon analytes (PAHs) were significantly better (asymmetry factors <1.3) when using the CWF sampling technique compared to splitless and on-column injection techniques (asymmetry factors >1.3). Extraction efficiencies for SPME (especially for high boiling point components such as PAHs) improved by an average of 2.5 times when using the CWF compared to the performance of commercially available SPME fibers. Coiled wire filaments and GC injection port liners were used for more than 100 Bacillus endospore thermochemolysis methylation analyses without the need for cleaning or replacement. [Copyright &y& Elsevier]