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.

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.

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 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.