Herbal supplement Spirulina stimulates inflammatory cytokine production in patients with dermatomyositis in vitro.

Spirulina, an herbal supplement and popular ingredient in health foods, is a potent stimulant of the immune system. Spirulina use is temporally associated with the onset or exacerbation of Dermatomyositis (DM), an autoimmune connective tissue disease that frequently affects the skin and muscle. In this study, we investigated the effect of Spirulina on peripheral blood mononuclear cells (PBMCs) in DM and Healthy Controls (HCs), showing that Spirulina stimulates Interferon ß (IFNß), Tumor necrosis factor α (TNFα), and Interferon γ (IFNγ) production of DM PBMCs primarily via Toll-Like Receptor 4 (TLR4) activation using ELISA (enzyme linked immunosorbent assay) and flow cytometry. We show that classical monocytes and monocyte-derived dendritic cells are stimulated by Spirulina and are activated via TLR4. Skin from patients with Spirulina-associated DM exhibits an inflammatory milieu similar to that of idiopathic DM but with a stronger correlation of TLR4 and IFNγ.

Cannabinoid type 2 receptor (CB2R) distribution in dermatomyositis skin and peripheral blood mononuclear cells (PBMCs) and in vivo effects of LenabasumTM.

BACKGROUND: Lenabasum is a cannabinoid type 2 receptor (CB2R) reverse agonist that demonstrates anti-inflammatory effects in vivo and in vitro in dermatomyositis (DM) and is currently being investigated for therapeutic potential. The purpose of our study is to investigate CB2R distribution as well as the effects of lenabasum in DM. METHODS: Immunohistochemistry staining (IHC) was utilized to examine immune cell and cytokine production changes in lesional DM skin biopsies from lenabasum and placebo-treated patients. CB2R expression in various immune cell populations within DM skin was investigated with image mass cytometry (IMC), whereas flow cytometry elucidated CB2R expression in DM peripheral blood mononuclear cells (PBMCs) as well as cytokine production by CB2R-expressing cell populations. RESULTS: After 12 weeks of lenabasum treatment, IHC staining showed that CD4+ T cells, CB2R, IL-31, IFN-γ, and IFN-ß cytokines were downregulated. IFN-γ and IFN-ß mRNA decreased in lesional DM skin but not in PBMCs. IMC findings revealed that CB2R was upregulated in DM lesional skin compared to HC skin and DM PBMCs (p<0.05). In DM skin, CB2R was upregulated on dendritic cells, B cells, T cells, and macrophages while dendritic cells had the greatest expression in both DM skin and PBMCs (p<0.05). These CB2R+ cells in the skin produce IL-31, IL-4, IFN-γ, and IFN-ß. CONCLUSION: Our findings of differential CB2R expression based on location and cell type suggest modes by which lenabasum may exert anti-inflammatory effects in DM and highlights dendritic cells as potential therapeutic targets.

Identification of Similarities Between Skin Lesions in Patients With Antisynthetase Syndrome and Skin Lesions in Patients With Dermatomyositis by Highly Multiplexed Imaging Mass Cytometry.

OBJECTIVE: Antisynthetase syndrome (ASyS) and dermatomyositis (DM) are autoimmune disorders that overlap clinically. Given the presence of DM-like skin lesions in ASyS patients, there is debate about whether ASyS is a distinct disease or a subclassification of DM. Recent studies identified differences in type I interferon (IFN) expression between ASyS and DM muscle and finger eruptions. This study was undertaken to elucidate similarities and differences in the pathogenesis of cutaneous disease in ASyS and DM at the single-cell level. METHODS: Five ASyS patients and 7 DM patients were recruited from a prospectively collected database of well-characterized DM patients. ASyS patients were clinically confirmed as having ASyS according to the Connors et al criteria and the Solomon et al criteria and the presence of aminoacyl-transfer RNA synthetase antibodies. Immunophenotyping was conducted using immunofluorescence (IF) and imaging mass cytometry (IMC). RESULTS: IF staining for MxA and IFNß expression revealed up-regulation of type I IFN in ASyS and DM samples compared to healthy control samples (P < 0.05). IMC showed similar numbers of macrophages, T cells, B cells, and dendritic cells in ASyS and DM samples, with no differences in counts (P > 0.05), but an increase in myeloid dendritic cell percentage in DM samples (P < 0.05). Key type I IFN, cytokine, and JAK/STAT pathways were similarly expressed in both ASyS and DM (P > 0.05). At the single-cell level, macrophages positive for phosphorylated stimulator of IFN genes in ASyS samples expressed increased levels of tumor necrosis factor, interluekin-17 (IL-17), and IFNß (P < 0.001). CONCLUSION: IMC is a powerful tool that identifies a role for the type I IFN system in DM-like skin lesions in ASyS and DM with some differences at the cellular level, but overall significant overlap, supporting similar therapeutic decision making.

Treatment Delay in Melanoma: A Risk Factor Analysis of an Impending Crisis.

Risk factors associated with melanoma treatment delay (MTD) have been inadequately studied. To elucidate MTD associations based on patient and tumor characteristics, a retrospective cohort study was performed for cutaneous melanoma cases reported to the National Cancer Database (NCDB) between 2004 and 2015. We evaluated the number of days from diagnosis to treatment initiation, analyzing postponements more than 45 days as moderate MTD (mMTD) and postponements more than 90 days as severe MTD (sMTD). Greater MTD rates were independently associated with patients who are older than 50 years, female, nonwhite, not privately insured, and treated at an academic facility and who have more advanced tumor stage and head/neck primaries.

Environmental triggers of dermatomyositis: a narrative review.

Dermatomyositis (DM) is an autoimmune disease that affects the skin, lungs, and muscle. Although the pathogenesis of DM is not completely understood, several environmental triggers have been linked to DM onset or flare. This article specifically examines the effects of herbal supplements, drugs, infections, ultraviolet (UV) radiation, and environmental pollutants on the onset or exacerbation of DM. Herbal supplements such as Spirulina platensis, Aphanizomenon flos-aquae, Chlorella, Echinacea, and Alfalfa have been implicated and are frequently used in health foods. Medications such as hydroxyurea, TNF-α inhibitors, immune checkpoint inhibitors (ICI), and penicillamine, as well as certain viral infections, such as parvovirus B19, coxsackie virus, polyomavirus, Epstein-Barr virus (EBV), hepatitis, influenza, and human immunodeficiency viruses (HIV) have been associated with DM onset. Bacterial infections and vaccinations have also been linked to the development of DM. Additional environmental factors, including UV radiation and air pollutants, such as silica, biological/mineral dust, and particulate air matter from vehicle and industrial emissions, may also play a role in DM pathogenesis. Overall, there is general agreement that an autoimmune attack of the skin, muscle, and lungs in DM can be triggered by various environmental factors and warrants further investigation.

Highly Multiplexed Mass Cytometry Identifies the Immunophenotype in the Skin of Dermatomyositis.

Dermatomyositis (DM) is a rare, systemic autoimmune disease that most frequently affects the skin, muscles, and lungs. The inflammatory infiltrate in the skin has not been fully characterized, and, in this study, we took a single-cell, unbiased approach using imaging mass cytometry. Substantial monocyte‒macrophage diversity was observed, with the CD14+ population correlating positively with Cutaneous Dermatomyositis Disease Area and Severity Index scores (P = 0.031). The T-cell compartment revealed CD4+ T, CD8+ T, and FOXP3+ T cells. Activated (CD69+) circulating memory T cells correlated positively with Cutaneous Dermatomyositis Disease Area and Severity Index scores (P = 0.0268). IFN-ß protein was highly upregulated in the T-cell, macrophage, dendritic cell, and endothelial cell populations of DM skin. Myeloid dendritic cells expressed phosphorylated peroxisome proliferator‒activated receptor γ, phosphorylated IRF3, IL-4, and IL-31, and their quantity correlated with itch as measured in Skindex-29. Plasmacytoid dendritic cells colocalized with IFN-γ in addition to the known colocalization with IFN-ß. Nuclear phosphorylated peroxisome proliferator‒activated receptor γ expression was found in the DM endothelium. Imaging mass cytometry allows us to characterize single cells in the immune cell population and identify upregulated cytokines and inflammatory pathways in DM. These findings have important implications for the development of future targeted therapies for DM.

Myeloid Dendritic Cells Are Major Producers of IFN-ß in Dermatomyositis and May Contribute to Hydroxychloroquine Refractoriness.

Dermatomyositis pathogenesis remains incompletely understood; however, recent work suggests a predominant IFN-1 response. We explored dermatomyositis pathogenesis by quantifying the inflammatory cells in the skin, comparing myeloid with plasmacytoid dendritic cell release of IFN-ß, and assessing myeloid dendritic cell (mDC) contribution to hydroxychloroquine refractoriness. Immunohistochemistry was performed to assess cell-type expression in lesional skin biopsies from 12 patients with moderate-to-severe cutaneous dermatomyositis. Immunofluorescence, laser-capture microdissection, and flow cytometry were used to assess mDC release of IFN-ß in lesional skin biopsies and blood of patients with dermatomyositis. Immunohistochemistry was utilized to determine whether myeloid or plasmacytoid dendritic cells were increased in hydroxychloroquine nonresponders. CD4+, CD11c+, and CD69+ cells were more populous in lesional skin of patients with dermatomyositis. mDCs colocalized with IFN-ß by immunofluorescence and laser-capture microdissection revealed increased IFN-ß mRNA expression by mDCs in lesional skin of patients with dermatomyositis. In blood, both mDCs and plasmacytoid dendritic cells were major producers of IFN-ß in patients with dermatomyositis, whereas plasmacytoid dendritic cells predominately released IFN-ß in healthy controls (P < 0.01). mDCs were significantly increased in the skin of hydroxychloroquine nonresponders compared with that in the skin of responders (P < 0.05). mDCs cells appear to play an important role in dermatomyositis pathogenesis and IFN-ß production.

Teledermatology Addressing Disparities in Health Care Access: a Review.

Purpose of Review: Dermatologists have been at the forefront of researching telemedicine to expand access to care. The current COVID-19 pandemic has prompted even greater expansion and implementation of teledermatology. This review discusses the research examining the potential impact of teledermatology addressing disparities in care. Recent Findings: Teledermatology appears to increase access to dermatology given expanded means to deliver care. Specifically, recent studies have found increased access among Medicaid-insured, resource-poor urban and rural, and elderly populations. Teledermatology implementation also facilitates education among providers at different levels of training. Still, as some patients have inconsistent access to the required technology, increased reliance on telemedicine may also potentially increase disparities for some populations. Summary: Teledermatology may serve to reduce disparities in health care access in many underserved and marginalized communities. Future research should continue to study implementation, especially given the expansion during the COVID-19 pandemic. Ultimately, teledermatology may play an important role in ensuring equitable care access for all.

Contact dermatitis: etiologies of the allergic and irritant type.

The term contact dermatitis describes an inflammatory process of the skin that occurs in response to contact with exogenous substances and involves pruritic and erythematous patches. Approximately 80% of all contact dermatitis is primary irritant contact dermatitis (ICD), whereas allergic contact dermatitis (ACD) makes up only 20% of contact dermatitis cases, the estimated prevalence of contact dermatitis in the United States being 1.4%. Among patch-tested patients, nickel has been identified as the most common allergen. Cobalt is the second most common metal allergen and is found in various dental alloys, paints, and coloring components of porcelain and glass. The average prevalence of dermatitis due to p-phenylenediamine (PPD) was found to be 4.3% in Asia, 4.0% in Europe, and 6.2% in North America. Rubber gloves are a major cause of occupational ACD in healthcare workers. Occupations involving frequent handwashing, between 20 and 40 times per day, have shown an increased incidence in cumulative ICD. The prevalence of occupational hand dermatitis was 69.7% in workers that reported a handwashing frequency exceeding 35 times per shift. The use of alcohol-based sanitizers is much more prevalent among today's healthcare workers than frequent handwashing. Both allergic and ICD are worldwide problems.

Gender differences in cutaneous melanoma: Demographics, prognostic factors, and survival outcomes.

Several recent studies have reported a considerably higher overall survival (OS) rate in females in various geographic regions This study further investigates the characteristics of melanoma that contribute to OS of women residing in the United States. Chi-square, Kaplan-Meier, and Cox regression models were used to analyze differences in demographics, treatment, and survival of invasive cutaneous melanoma in men and women diagnosed from 2004 to 2016 in the National cancer database. In 316 966 patients met inclusion criteria. Men had a significantly higher median age of diagnosis at 61 years (interquartile range or IQR: 51-72) in comparison to women where the median age of diagnosis was 55 years (IQR: 43-68) (P < .0001). The most common primary site for men was the trunk (35.5%), whereas the lower extremities were the most common primary site for women (30.3%). Women had a higher 5 year (82.6%) and 10 year (73.1%) OS compared to 5 year and 10 year OS of 72.2% and 58.7%, respectively, in men (P < .0001). When adjusting for confounders, female gender was independently associated with improved OS (ref: male HR = 0.791; 95% confidence interval 0.773-0.809; P < .0001). Overall, we conclude that female gender is an independent favorable prognostic factor for melanoma survival.

A Qualitative Analysis of Malpractice Litigation in Cardiology Using Case Summaries Through a National Legal Database Analysis.

Introduction Physicians are increasingly practicing defensive medicine as a response to society's litigious climate. This study sought to characterize cardiology malpractice claims and elucidate the allegations underlying the use of defensive medicine. Methods The WestlawNext™ database was queried to obtain state and federal jury verdicts and settlements related to medical malpractice and cardiology that occurred in the United States between 2010 and 2015. Cardiology cases were identified using the search terms "medical malpractice" and "cardiology" and reviewed by two individuals utilizing available case documents. Duplicate and nonpertinent cases were excluded. Binary logistic regression models were created to predict the likelihood of defendant verdict, plaintiff verdict, and settlement based on the various reasons for litigation cited. Results Inclusion criteria were met in 166 cases. The plaintiffs were predominantly male (94 cases; 56.6%), and the average patient age was 53.3±17.5 years. More than half of the cases involved a cardiologist as a defendant. The most common reasons for litigation were: failure to treat (129; 77.7%), failure to diagnose (115; 69.3%), failure to refer/order diagnostic tests (107; 64.5%), and patient death (118; 71.1%). Among cases tried for failure to diagnose, the most commonly missed diagnosis was myocardial infarction. Cases most commonly resulted in a defendant verdict (94; 56.6%). However, odds of a plaintiff verdict were significantly higher when failure to diagnose was alleged with an odds ratio (OR) of 7.60 (95% confidence interval 1.14 - 50.87, p = 0.0365). Conclusions Failure to diagnose remains a commonly alleged base for litigation. In conclusion, our analysis suggests increased training for non-cardiologists in the recognition of the acute coronary syndrome and enhanced awareness of inherent biases among all physicians may facilitate reducing missed diagnoses.

The physiology of melanin deposition in health and disease.

Eumelanin is the major pigment responsible for human skin color. This black/brown pigment is localized in membrane-bound organelles (melanosomes) found in specialized cells (melanocytes) in the basal layer of the epidermis. This review highlights the steps involved in melanogenesis in the epidermis and the disorders in skin pigmentation that occur when specific steps critical for this process are defective. Melanosomes, which contain tyrosinase, a major enzyme involved in melanin synthesis, develop through a series of steps in the melanocyte. They are donated from the melanocyte dendrites to the surrounding keratinocytes in the epidermis. In the keratinocytes, the melanosomes are found singly or packaged into groups, and as the keratinocytes move upward in the epidermis, the melanosomes start to degrade. This sequence of events is critical for melanin pigmentation in the skin and can be influenced by genetic, hormonal, and environmental factors, which all play a role in levels of melanization of the epidermis. The effects these factors have on skin pigmentation can be due to different underlying mechanisms involved in the melanization process leading to either hypo- or hyperpigmentary disorders. These disorders highlight the importance of mechanistic studies on the specific steps involved in the melanization process.

A Large Skin Cancer Screening Quality Initiative: Description and First-Year Outcomes.

IMPORTANCE: The lack of prospective randomized clinical trials demonstrating that full-body skin examination (FBSE) reduces melanoma morbidity or mortality has prompted an "I" rating from the United States Preventive Services Task Force for population-based skin cancer screening. More data on these screening programs are needed. OBJECTIVES: To describe a skin cancer screening quality initiative in a large health care system and to determine if the intervention was associated with screening of a demographically higher-risk population than previous screening programs and if melanoma incidence and thickness differed in screened vs unscreened patients. DESIGN, SETTING, AND PARTICIPANTS: This observational evaluation of a prospectively implemented quality initiative was conducted in a large health care system in western Pennsylvania (University of Pittsburgh Medical Center, UPMC) among adults seen in an office visit by a UPMC-employed primary care physician (PCP) in 2014. INTERVENTIONS: Implementation of a campaign promoting annual skin cancer screening by FBSE, including training of PCPs, promotion of the initiative to physicians and patients, and modification of the electronic health record (EHR) to include FBSE as a recommended preventive service for patients 35 years or older. MAIN OUTCOMES AND MEASURES: Characteristics of screened and unscreened patients and melanomas detected among them. RESULTS: Of 333 735 adult patients seen in an office visit by PCPs in 2014, 53 196 patients (15.9% of the screen-eligible population) received an FBSE, and 280 539 did not. Screened patients were slightly older (median age, 60 vs 57 years; P < .001) but did not differ significantly by sex (43.2% vs 43.1% men; P = .49) from the unscreened population. Fifty melanomas were diagnosed in screened patients and 104 melanomas were diagnosed in unscreened patients. Screened patients were more likely than unscreened patients to be diagnosed with melanoma (adjusted risk ratio [RR], 2.4; 95% CI, 1.7-3.4; P < .001) and to have a thinner invasive melanoma (median thickness, 0.37 mm vs 0.65 mm; P < .001). The incidence of melanoma lesions 1 mm or thicker was similar in screened vs unscreened patients (adjusted RR, 0.7; 95% CI, 02.-2.2; P = .52). CONCLUSIONS AND RELEVANCE: Large-scale screening for melanoma within a United States health care system is feasible and can result in increased detection of thinner melanomas. This intervention also resulted in screening of a higher proportion of men and an older patient population than previous screening interventions in which younger individuals and women predominated.