Single-cell RNA sequencing of psoriatic skin identifies pathogenic Tc17 cell subsets and reveals distinctions between CD8+ T cells in autoimmunity and cancer.

BACKGROUND: Psoriasis is an inflammatory, IL-17-driven skin disease in which autoantigen-induced CD8+ T cells have been identified as pathogenic drivers. OBJECTIVE: Our study focused on comprehensively characterizing the phenotypic variation of CD8+ T cells in psoriatic lesions. METHODS: We used single-cell RNA sequencing to compare CD8+ T-cell transcriptomic heterogeneity between psoriatic and healthy skin. RESULTS: We identified 11 transcriptionally diverse CD8+ T-cell subsets in psoriatic and healthy skin. Among several inflammatory subsets enriched in psoriatic skin, we observed 2 Tc17 cell subsets that were metabolically divergent, were developmentally related, and expressed CXCL13, which we found to be a biomarker of psoriasis severity and which achieved comparable or greater accuracy than IL17A in a support vector machine classifier of psoriasis and healthy transcriptomes. Despite high coinhibitory receptor expression in the Tc17 cell clusters, a comparison of these cells with melanoma-infiltrating CD8+ T cells revealed upregulated cytokine, cytolytic, and metabolic transcriptional activity in the psoriatic cells that differed from an exhaustion program. CONCLUSION: Using high-resolution single-cell profiling in tissue, we have uncovered the diverse landscape of CD8+ T cells in psoriatic and healthy skin, including 2 nonexhausted Tc17 cell subsets associated with disease severity.

The impact of pediatric atopic dermatitis on families: A review.

BACKGROUND: Atopic dermatitis (AD) is an extremely common childhood disease, with considerable impact on the quality of life of affected children and their families. While pruritus is the hallmark symptom of this disease, AD has been well-documented to impact patients beyond physical symptoms, resulting in behavior problems, mood disorders, and sleep disturbance. OBJECTIVE: This literature review outlines how atopic dermatitis impacts the quality of life of families of children affected by AD. METHODS: A total of 3436 articles were identified via an online search of the MEDLINE health literature database and were screened for relevance to quality of life impacts on families with children affected by AD. RESULTS: Caring for children affected by AD can be an extremely time-consuming task that can impair personal relationships, decrease psychosocial functioning, and cause sleep loss among family members of affected patients. Additionally, AD may result in work absence or decreased work productivity for caregivers. Special diets, irritant and allergen avoidance strategies, and alternative therapies are commonly used by patients to manage their disease and require large amounts of family involvement. CONCLUSIONS: Atopic dermatitis can greatly decrease quality of life of families of affected children in various domains, including sleep, finances, and relationships. Early intervention and psychotherapy may be needed in some patients to address these quality of life impairments.

Transgenic expression of human amphiregulin in mouse skin: inflammatory epidermal hyperplasia and enlarged sebaceous glands.

To explore the role of amphiregulin in inflammatory epidermal hyperplasia, we overexpressed human AREG (hAREG) in FVB/N mice using a bovine K5 promoter. A construct containing AREG coding sequences flanked by 5' and 3' untranslated region sequences (AREG-UTR) led to a >10-fold increase in hAREG expression compared to an otherwise-identical construct containing only the coding region (AREG-CDR). AREG-UTR mice developed tousled, greasy fur as well as elongated nails and thickened, erythematous tail skin. No such phenotype was evident in AREG-CDR mice. Histologically, AREG-UTR mice presented with marked epidermal hyperplasia of tail skin (2.1-fold increase in epidermal thickness with a 9.5-fold increase in Ki-67(+) cells) accompanied by significantly increased CD4+ T-cell infiltration. Dorsal skin of AREG-UTR mice manifested lesser but still significant increases in epidermal thickness and keratinocyte hyperplasia. AREG-UTR mice also developed marked and significant sebaceous gland enlargement, with corresponding increases in Ki-67(+) cells. To determine the response of AREG-UTR animals to a pro-inflammatory skin challenge, topical imiquimod (IMQ) or vehicle cream was applied to dorsal and tail skin. IMQ increased dorsal skin thickness similarly in both AREG-UTR and wild type mice (1.7- and 2.2-fold vs vehicle, P < 0.001 each), but had no such effect on tail skin. These results confirm that keratinocyte expression of hAREG elicits inflammatory epidermal hyperplasia, and are consistent with prior reports of tail epidermal hyperplasia and increased sebaceous gland size in mice expressing human epigen.

A Pilot Study to Assess the Reliability of Digital Image-Based PASI Scores Across Patient Skin Tones and Provider Training Levels.

INTRODUCTION: The ability to perform psoriasis skin assessments remotely through digital image-based psoriasis area and severity index (DIB-PASI) would be a valuable tool for psoriasis clinical trials. An ideal teledermatological assessment would be robust across patients of diverse skin tones as well as across assessors of varying experience levels. In this pilot study, we evaluated the reliability of face-to-face (FTF) versus DIB-PASI scores determined by trained clinical assessors with a spectrum of experience and with patients of different skin tones. METHODS: Fourteen subjects of varying skin tones with moderate-to-severe plaque psoriasis were treated with adalimumab. In-person PASI assessments and digital photography were performed in the clinic at weeks 0, 12, and 24. Photographs were reviewed by four independent assessors to derive a digital image-based PASI score. The concordance of face-to-face PASI (FTF-PASI) and DIB-PASI were analyzed across patient and assessor factors. RESULTS: Overall concordance between FTF-PASI and DIB-PASI was high (ICC 0.82, p < 0.0001), with good agreement across individual assessors. When analyzed by PASI score component or body region, digital assessors also demonstrated good agreement with the FTF assessor. Similarly, DIB-PASI showed high concordance with FTF-PASI for patients with light skin tones and patients with medium-to-dark skin tones, and across clinical training levels. CONCLUSION: Overall, PASI scores derived from digital images showed good agreement with those determined in person. Importantly, these remote assessments were reliable for both light and medium-to-dark skin tones, and robust to training level of the assessor. The findings from this pilot study lay the foundation for expanding teledermatology-based clinical trials for patients with psoriasis and enabling accurate, remote monitoring of disease severity and therapy response.

Transcriptomic Profiling of Plaque Psoriasis and Cutaneous T-Cell Subsets during Treatment with Secukinumab.

The IL-17A inhibitor secukinumab is efficacious for the treatment of psoriasis. To better understand its mechanism of action, we investigated its impact on psoriatic lesions from 15 patients with moderate-to-severe plaque psoriasis undergoing secukinumab treatment. We characterized the longitudinal transcriptomic changes of whole lesional skin tissue as well as cutaneous CD4+ and CD8+ T effector cells and CD4+ T regulatory cells across 12 weeks of treatment. Secukinumab was clinically effective and reduced disease-associated overexpression of IL17A , IL17F, IL23A, IL23R, and IFNG in whole tissue as soon as 2 weeks after initiation of treatment. IL17A overexpression in T-cell subsets, primarily CD8+ T cells, was also reduced. Although secukinumab treatment resolved 89‒97% of psoriasis-associated expression differences in bulk tissue and T-cell subsets by week 12 of treatment, we observed expression differences involved in IFN signaling and metallothionein synthesis that remained unresolved at this time point as well as potential treatment-associated expression differences involved in IL-15 signaling. These changes were accompanied by shifts in broader immune cell composition on the basis of deconvolution of RNA-sequencing data. In conclusion, our study reveals several phenotypic and cellular changes within the lesion that underlie clinical improvement from secukinumab.

Review of Post-laser-resurfacing Topical Agents for Improved Healing and Cosmesis.

BACKGROUND: Laser resurfacing produces a controlled skin injury, resulting in a wound healing response. This wound healing response allows for collagen remodeling, which improves skin texture and tone. Topical agents are often employed following laser treatments to facilitate recovery. The introduction of newer small-molecule technologies allow for improved recovery and cosmesis. OBJECTIVE: We sought to perform a critical review of the safety and efficacy of newer small-molecule technologies employed following laser resurfacing. METHODS: We performed a PubMed search of the generic name of the following topicals and included literature relevant to laser procedures, with an emphasis on laser resurfacing: thermal spring water, conjugated linolenic acid, vitamin C/vitamin E/ferulic acid serum, tripeptide/hexapeptide technology-containing products, growth factor serum and gel, recombinant human epidermal growth factor ointment and gel, red deer umbilical cord lining mesenchymal stem cell extract cream and serum, silicone-based gel, and microparticulate (1-3, 1-6 beta-glucan) gel. RESULTS: Our search of the PubMed database yielded 62 results, out of which 17 clinical studies were included in this publication. The majority of aforementioned topicals show promise in terms of improving post-resurfacing recovery or cosmesis. CONCLUSION: Clinical data regarding these agents is limited by the number and quality of studies. It is therefore challenging to propose a recommendation supporting any particular topical. We provide our own provider-specific post-laser resurfacing protocols to offer insight regarding new small-molecule technologies.

Non-pharmacologic approaches for hidradenitis suppurativa - a systematic review.

Importance: Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition presenting with painful nodules and sinus tracts primarily in intertriginous regions. The persistent nature of HS and challenges in symptom management lead many patients to seek non-pharmacologic approaches due to the paucity and limited efficacy of conventional HS therapeutic options.Objective: To evaluate the existing evidence for non-pharmacologic modalities in treatment of HS.Findings: Discussed in this review are non-pharmacologic modalities with evidence of efficacy in HS treatment, including weight loss, vitamin B12, vitamin D and zinc supplementation, and dietary avoidance of brewer's yeast. Limitations of the available data on non-pharmacologic therapies in HS include the predominance of pilot and single-armed studies, as well as heterogeneity in study design, subject disease severity, concomitant treatment and comorbid conditions.Conclusions and relevance: HS patients are becoming increasingly interested in the use of non-pharmacologic approaches to augment conventional treatments. Strength of evidence for non-pharmacologic therapies in HS is limited by small study size and lack of randomized controlled trials. Future large-scale investigations should be pursued to better establish efficacy and dosing regimens for the use of non-pharmacologic treatments in HS.

Implementation of an Ultraviolet Phototherapy Service at a National Referral Hospital in Western Kenya: Reflections on Challenges and Lessons Learned.

INTRODUCTION: In order to manage skin conditions at a national referral hospital level in Kenya, specialized dermatology services, such as dermatologic surgery, dermatopathology, phototherapy, and sub-specialty care, should be offered, as is typically available in referral hospitals around the world. A Kenyan patient with prurigo nodularis, whose severe itch remitted after phototherapy treatment at the University of California, San Francisco (UCSF), inspired the development of a phototherapy service at Academic Model Providing Access to Healthcare (AMPATH), a partnership in Western Kenya between Moi Teaching and Referral Hospital, Moi University College of Health Sciences, and a consortium of North American academic medical centers. METHODS: Initial project funds were raised through a crowdfunding campaign and fundraising events. A new narrowband ultraviolet B phototherapy unit and replacement bulbs were donated and air shipped to Eldoret, Kenya. A team of dermatologists and phototherapy nurses from UCSF conducted a 2-day training session. US-based dermatologists affiliated with AMPATH provide ongoing support through regular communication and on-site visits. RESULTS: Early in implementation, challenges faced included training clinical staff with limited experience in phototherapy and improving communication between nurses and clinicians. More recent challenges include frequent rotation of specialty clinic nurses in the dermatology clinic, adaptation of phototherapy guidelines to balance patient volume with service delivery capacity, and training assessment of disease activity in darkly pigmented skin. CONCLUSION: Strategies that have been helpful in addressing implementation challenges include: increasing on-site and remote training opportunities for clinicians and nurses, developing a tiered payment schema, educating patients to combat misconceptions about phototherapy, dynamic phototherapy referral guidelines to accommodate service delivery capacity, and prioritizing the engagement of a multidisciplinary team.

Psychopharmacology.

Most dermatologists evaluate and treat patients with psychological or psychiatric issues related to their skin disease. These patients often require psychopharmacologic therapies. Therefore, it is important for dermatologists to be familiar with psychopharmacologic treatments for diseases that fit into the overlap between psychiatry and dermatology. This review aims to provide a concise overview of psychopharmacology as it applies to dermatology. Psychotropic medications commonly used in psychodermatology, including antidepressants, antipsychotics, and anxiolytics, are reviewed; safety profile and dosing recommendations are discussed.

Recent Developments in Atopic Dermatitis.

Atopic dermatitis (AD) is a bothersome and common skin disease affecting ∼10.7% of children in the United States. This skin condition significantly decreases quality of life in not only patients, but in their families as well. Pediatricians are often the first physicians to diagnose and manage these patients and thus are relied on by families to answer questions about this disease. AD is complex, multifactorial, and has historically had limited therapeutic options, but the landscape of this disease is now rapidly changing. Pathways contributing to the pathogenesis of this disease are continually being discovered, and new therapies for AD are being developed at an unprecedented rate. With this article, we will review the current guidelines regarding the management of AD, outline updates in the current understanding of its pathophysiology, and highlight novel developments available for the treatment of this burdensome disease.

Neuromodulation in Inflammatory Skin Disease.

Inflammatory skin diseases are difficult to treat because of a lack of available treatment options for severe disease. However, recent advances have shown that vagus nerve stimulation can be used to decrease inflammation and reduce disease severity in rheumatoid arthritis and inflammatory bowel disease. Changes in cytokine profiles observed in these studies are similar to those seen with use of biologics in inflammatory skin disease, suggesting that they act along similar pathways to disrupt chronic inflammation and treat inflammatory disease. This commentary explores the existing evidence demonstrating the efficacy of neuromodulation in inflammatory disease, and outlines reasons why these findings could translate to the dermatology setting to treat inflammatory skin disease.

Review of the mechanism of action of coal tar in psoriasis.

PURPOSE: Crude coal tar and its derivatives have been used in modern medicine for the treatment of psoriasis since at least 1925 as part of the Goeckerman regimen. To this day, coal tar remains a safe and highly effective option for the treatment of psoriasis vulgaris. However, the mechanism by which coal tar has its therapeutic effect is unknown. This review summarizes current knowledge of the mechanism by which coal tar has its therapeutic effect in the treatment of psoriasis vulgaris. MATERIAL AND METHODS: A Pubmed search was conducted on March 13, 2017 for relevant English language journal articles on the subject and were relevant journal articles were included in this review. RESULTS: Crude coal tar consists of thousands of ingredients, many of which are unidentified. Of these ingredients, the most research has gone into analyzing polycyclic aryl hydrocarbons. These hydrocarbons are thought to be the most likely component of crude coal tar that leads to its effects in psoriasis. Of the aryl hydrocarbons, carbazole has been the most well studied in psoriasis and is hypothesized as being responsible for the treatment efficacy of crude coal tar. CONCLUSIONS: Polycyclic aryl hydrocarbons, and specifically carbazole, are thought to be the mechanism by which crude coal tar has its effect in psoriasis. However, further research is warranted to fully characterize the mechanism of action of crude coal tar, with the potential to create new therapies for psoriasis.

Guselkumab for the treatment of moderate-to-severe plaque psoriasis.

INTRODUCTION: Guselkumab is a human monoclonal antibody targeting the p19 subunit of IL-23 that has been approved for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. This medication blocks the IL-23/IL-17 axis, which has been implicated in playing a key role in the pathogenesis of psoriasis. Areas covered: This review outlines the pharmacologic properties, safety, and efficacy of guselkumab for the treatment of plaque psoriasis. Expert commentary: Guselkumab is the first IL-23 specific inhibitor to be approved for the treatment of plaque psoriasis. Phase II and III clinical trial results have demonstrated excellent safety and efficacy of guselkumab. IL-23 inhibitors may offer potential benefits over existing therapies for moderate-to-severe plaque psoriasis in terms of safety, frequency of administration, and efficacy. Long-term safety data will be critical in evaluating the role of guselkumab in the treatment of psoriasis.

Patch testing for adverse drug reactions.

Adverse drug reactions result in a substantial number of hospital admissions and inpatient events. Diagnosis usually is made with clinical judgment and circumstantiality without diagnostic testing. Furthermore, even in situations where diagnostic testing is performed, no safe gold standard tests exist. Oral rechallenge is currently the gold standard but carries the risk of recrudescence of severe allergic symptoms. Other tests include skin prick tests, the lymphocyte transformation test, immunohistochemistry, and patch testing. This article provides a review of patch testing in cases of adverse drug reactions and presents new data on this topic.

Monoclonal antibodies inhibiting IL-12, -23, and -17 for the treatment of psoriasis.

Psoriasis is a chronic, inflammatory, immune-mediated skin condition that affects 3 to 4% of the adult US population, characterized by well-demarcated, erythematous plaques with silver scale. Psoriasis is associated with many comorbidities including cardiometabolic disease and can have a negative impact on quality of life. The current armamentarium of psoriasis treatment includes topical therapies, phototherapy, oral immunosuppressive therapies, and biologic agents. Over the past 2 decades, there has been rapid development of novel biologic therapies for the treatment of moderate-to-severe plaque psoriasis. This article will review the role of IL-12, IL-23, and IL-17 in the pathogenesis of psoriasis and the monoclonal antibodies (ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, and risankizumab) that target these cytokines in the treatment of this disease.

Clinical utility of ixekizumab in the treatment of moderate-to-severe plaque psoriasis.

Psoriasis vulgaris is a chronic, immune-mediated systemic disease that affects7.5 million people in the US. It can be treated with many therapies, often in combination, which include topicals, phototherapy, oral systemics, and biologics. Biologic agents target specific components of the immune system involved in the pathogenesis of psoriasis including TNF-alpha, IL-12, IL-17, and IL-23. The biologic ixekizumab, approved for the treatment of moderate-severe plaque psoriasis in the US, targets IL-17. This review describes the role of IL-17 in psoriasis, the mechanism by which ixekizumab targets this cytokine, and the clinical utility of ixekizumab.

Frequency and Management of Sleep Disturbance in Adults with Atopic Dermatitis: A Systematic Review.

INTRODUCTION: Intense nocturnal pruritus as well as the complex pathophysiology of atopic dermatitis (AD) can severely affect sleep and become a major factor in negatively impacting quality of life in adults. However, much of the literature on sleep disturbance in AD patients is on the pediatric population, and it is not well studied in adults. Furthermore, limited studies are available to guide effective management of sleep disturbance in AD in general. We review the literature to present the studies that have investigated the relationship between AD and its effect on sleep in adults and provide an approach for clinicians caring for this population. METHODS: A systematic literature search was conducted through the PubMed and EMBASE databases using the search terms "atopic dermatitis" OR "eczema" AND "sleep." The articles generated by the search and their references were reviewed. RESULTS: A high prevalence of sleep disturbance is experienced by adults with AD. The likelihood of sleep disturbance is much higher in patients with AD compared to those without AD. Sleep disturbance appears to worsen with AD severity. Pruritus and scratching appear to be large contributors to sleep disturbance in adult patients with AD. CONCLUSION: It is important that clinicians evaluate the severity of AD and ask general questions about itching, sleep, impact on daily activities, and persistence of disease during each patient visit and follow-up with the complaint of sleep disturbance. Management of sleep disturbance in AD should focus on adequate disease control of AD as well as possible medical interventions to help improve sleep. The pathophysiology of sleep disturbance in AD is extremely complex, and further research is needed to better understand the interplay of the immune system, circadian rhythm, and environmental factors implicated in both AD and sleep.

Guselkumab for the Treatment of Psoriasis: A Review of Phase III Trials.

INTRODUCTION: Interleukin (IL)-23 inhibitors are a new class of biologics currently undergoing clinical trials for the treatment of moderate-to-severe psoriasis. Phase III studies of guselkumab, an IL-23 receptor monoclonal antibody, are currently underway. METHODS: We summarize the available phase III results to date, establishing the efficacy and safety of guselkumab in patients with moderate-to-severe plaque psoriasis. RESULTS: Currently, there are available data of up to 48 weeks from two Phase III, multicenter, randomized, double-blind, placebo- and comparator-controlled clinical trials, VOYAGE 1 and VOYAGE 2. At week 16, the proportion of patients attaining at least a 90% improvement from baseline in the Psoriasis Area and Severity Index (PASI 90) was 73.3% in VOYAGE 1 and 70.0% in VOYAGE 2. Guselkumab remained efficacious through 48 weeks of treatment. Guselkumab maintained a satisfactory safety profile with the most frequently reported adverse events being nasopharyngitis, headache, and upper respiratory tract infection. CONCLUSION: Phase III trials of Guselkumab suggest a favorable efficacy and safety profile of this novel drug. Although further studies are needed to assess long-term safety and efficacy, based on the results to date, guselkumab appears to be a promising therapeutic option for moderate-to-severe plaque-type psoriasis.