Demonstration of Convolutional Neural Networks to Determine Patch Test Reactivity.

Background: Convolutional neural networks (CNNs) have the potential to assist allergists and dermatologists in the analysis of patch tests. Such models can help reduce interprovider variability and improve consistency of patch test interpretations. Objective: Our aim is to evaluate the performance of a CNN model as a proof of concept in discriminating between patch tests with reactions and patch tests without reactions. Methods: We performed a retrospective analysis of patch test images from March 2020 to March 2021. The CNN model was trained as a binary classifier to discriminate between reaction and nonreaction patches. Performance of the model was determined using summary statistics and receiver operator characteristics (ROC) curves. Results: In total, 13,622 images from 125 patients were recorded for analysis. The majority of patients in the cohort were female (81.6%) with Fitzpatrick skin types I-II (88.0%). The area under curve was 0.940, indicating a high discriminative performance of the model for this data set. This resulted in a total accuracy of 90.1%, sensitivity of 86.0%, and specificity of 90.2%. Conclusions: CNNs have the capacity to determine the presence of delayed-type reactions in patch tests. Future prospective studies are required to assess the generalizability of such models.

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.

Validation of a Proprietary Deterioration Index Model and Performance in Hospitalized Adults.

Importance: The Deterioration Index (DTI), used by hospitals for predicting patient deterioration, has not been extensively validated externally, raising concerns about performance and equitable predictions. Objective: To locally validate DTI performance and assess its potential for bias in predicting patient clinical deterioration. Design, Setting, and Participants: This retrospective prognostic study included 13 737 patients admitted to 8 heterogenous Midwestern US hospitals varying in size and type, including academic, community, urban, and rural hospitals. Patients were 18 years or older and admitted between January 1 and May 31, 2021. Exposure: DTI predictions made every 15 minutes. Main Outcomes and Measures: Deterioration, defined as the occurrence of any of the following while hospitalized: mechanical ventilation, intensive care unit transfer, or death. Performance of the DTI was evaluated using area under the receiver operating characteristic curve (AUROC) and area under the precision recall curve (AUPRC). Bias measures were calculated across demographic subgroups. Results: A total of 5 143 513 DTI predictions were made for 13 737 patients across 14 834 hospitalizations. Among 13 918 encounters, the mean (SD) age of patients was 60.3 (19.2) years; 7636 (54.9%) were female, 11 345 (81.5%) were White, and 12 392 (89.0%) were of other ethnicity than Hispanic or Latino. The prevalence of deterioration was 10.3% (n = 1436). The DTI produced AUROCs of 0.759 (95% CI, 0.756-0.762) at the observation level and 0.685 (95% CI, 0.671-0.700) at the encounter level. Corresponding AUPRCs were 0.039 (95% CI, 0.037-0.040) at the observation level and 0.248 (95% CI, 0.227-0.273) at the encounter level. Bias measures varied across demographic subgroups and were 14.0% worse for patients identifying as American Indian or Alaska Native and 19.0% worse for those who chose not to disclose their ethnicity. Conclusions and Relevance: In this prognostic study, the DTI had modest ability to predict patient deterioration, with varying degrees of performance at the observation and encounter levels and across different demographic groups. Disparate performance across subgroups suggests the need for more transparency in model training data and reinforces the need to locally validate externally developed prediction models.

Anti-transcription intermediary factor 1-gamma IgG2 isotype is associated with cancer in adult dermatomyositis: an ENMC multinational study.

OBJECTIVE: To assess the role of the anti-TIF1γ auto-antibody (aAb) IgG2 isotype as a biomarker of cancer in anti-TIF1γ aAb-positive adult DM. METHODS: International multicentre retrospective study with the following inclusion criteria: (i) diagnosis of DM according to ENMC criteria; (ii) presence of anti-TIF1γ IgG aAb determined using an in-house addressable laser bead immunoassay (ALBIA) from cryopreserved serums sampled at time of DM diagnosis and (iii) available baseline characteristics and follow-up data until the occurrence of cancer and/or a minimum follow-up of 1 year for patients without known cancer at diagnosis. Detection and quantification of anti-TIF1γ IgG2 aAb was done using the in-house ALBIA. In addition, a recent ELISA commercial kit was used for anti-TIF1γ IgG aAb quantification. RESULTS: A total of 132 patients (mean age 55±15 years) of whom 72 (54.5%) had an associated cancer were analysed. The association between the presence of cancer and the presence of anti-TIF1γ IgG2 aAb was statistically significant (P = 0.026), with an OR of 2.26 (95% CI: 1.10, 4.76). Patients with cancer displayed significantly higher anti-TIF1γ IgG2 aAb ALBIA values with a median value of 1.15 AU/ml (IQR: 0.14-9.76) compared with 0.50 AU/ml (IQR: 0.14-1.46) for patients without cancer (P = 0.042). In addition, patients with cancer displayed significantly higher anti-TIF1γ IgG aAb ELISA values with a median value of 127.5 AU/ml (IQR: 81.5-139.6) compared with 93.0 AU/ml (IQR: 54.0-132.9) for patients without cancer (P = 0.004). CONCLUSION: These results suggest considering anti-TIF1γ IgG2 ALBIA and IgG ELISA values as biomarkers of cancer in anti-TIF1 γ aAb-positive adult DM.

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.

Trends in Patch Testing in the Medicare Part B Fee-for-Service Population.

BACKGROUND: Patch testing is a vital component of the workup for allergic contact dermatitis. There are limited data on changes of patch testing use among Medicare providers, as well as patch testing reimbursement rates. OBJECTIVE: The aim of the study was to evaluate trends in the use of patch testing among various Medicare providers and Medicare patch testing reimbursement. DESIGN: A longitudinal analysis of patch testing claims was performed with the Medicare Part B Physician/Supplier Procedure Summary files from 2010 to 2018. The primary outcomes were the total number and change in the number of submitted patch testing services from 2010 to 2018 by 3 provider groups: dermatology physicians, nondermatology physicians, and nonphysician providers. Secondary outcome measures included Medicare reimbursement amounts and changes in reimbursement amounts for patch test services (total and per 1000 enrollees) from 2010 to 2018 for the 3 provider groups, as well as per patch test service. RESULTS: From 2010 to 2018, submitted patch testing services per 1000 enrollees grew by 89.0%. The annual trend estimate for submitted services relative to 2010 was +10.1% (95% confidence interval [CI] = 8.1 to 12.0) for physicians and +34.1% (95% CI = 32.1 to 36.0) for nonphysician providers (physician assistants and nurse practitioners). Among physicians, the annual trend estimate for submitted services was +5.1% (95% CI = -11.3 to 21.5) for dermatologists and +31.40% (95% CI = 15.00 to 47.81) for allergists. CONCLUSIONS: Patch testing increased in the US Medicare population from 2010 to 2018, and this increase was largely driven by nonphysician providers and allergists.

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.

Plasma-derived DNA containing-extracellular vesicles induce STING-mediated proinflammatory responses in dermatomyositis.

Objectives: Extracellular vesicles (EVs) are lipid bilayer membrane vesicles that are present in various bodily fluids and have been implicated in autoimmune disease pathogenesis. Type I interferons (IFN), specifically IFN-ß, are uniquely elevated in dermatomyositis (DM). The stimulator of interferon genes (STING) works as a critical nucleic acid sensor and adaptor in type I IFN signaling with possible implications in autoimmune diseases such as DM. In the current study, we investigated whether circulating EVs contribute to proinflammatory effects in DM, whether these proinflammatory responses are mediated by the STING signaling pathway, and if so, by what mechanism STING is activated. Methods: We collected and characterized EVs from plasma of healthy controls (HC) and DM patients; analyzed their abilities to trigger proinflammatory cytokines release by ELISA, and explored STING signaling pathway activation using immunoblot and immunofluorescent staining. STING signaling pathway inhibitors and RNAi were used to further investigate whether STING was involved in EVs-triggered proinflammatory response. DNase/lipid destabilizing agent was utilized to digest EVs and their captured DNA contents to evaluate how EVs triggered STING-mediated proinflammatory response in DM. Results: EVs isolated from DM plasma triggered proinflammatory cytokines including type I IFN release with STING signaling pathway activation. The activated STING pathway was preferentially mediated by dsDNA captured by EVs. Suppression of STING or its downstream signaling proteins attenuated the EVs-mediated proinflammatory response. Conclusions: Plasma-derived, DNA containing-EVs induced STING-mediated proinflammatory effects in DM. Targeting the STING pathway may be a potential therapeutic approach for DM.

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.

Increased MxA protein expression and dendritic cells in spongiotic dermatitis differentiates dermatomyositis from eczema in a single-center case-control study.

BACKGROUND: Dermatomyositis (DM) is conventionally characterized by interface dermatitis (ID) on skin histopathology. A subset of DM patients has skin biopsies showing spongiotic dermatitis (SD), a histopathology more commonly seen in eczema. In this study, we aimed to (a) identify the percentage of clinically diagnosed DM patients with SD skin biopsies, (b) identify cytokine and cell markers that can help determine if a SD skin biopsy is consistent with DM. METHODS: In this case-control study, biopsy specimens from ten DM patients with SD (DM-SD) were compared to specimens from ten healthy controls, ten patients with eczema, and 12 patients with DM with ID (DM-ID). Specimens were stained by immunohistochemistry for MxA, IFN-ß, CD11c, and BDCA2. One-way ANOVA with Bonferroni's multiple comparison test was used to compare protein expression between groups. RESULTS: Eleven of 164 (6.7%) patients with a clinical diagnosis of DM at our tertiary care center were identified as having SD. MxA, IFN-ß, CD11c, and BDCA2 protein expression was significantly higher in DM-SD compared to eczema and healthy controls. Expressions of MxA, IFN-ß, and BDCA2 were not significantly different between DM-SD and DM-ID. CONCLUSION: Increased MxA, IFN-ß, CD11c, and BDCA2 protein expression may aid in distinguishing between DM-SD and eczema and warrants further investigation.

Sensitivity of Volumetric Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy to Progression of Spinocerebellar Ataxia Type 1.

BACKGROUND: Spinocerebellar ataxia type 1 (SCA1) causes progressive degeneration of the cerebellum and brainstem. Volumetric magnetic resonance imaging (MRI) was shown to be more sensitive to disease progression than the most sensitive clinical measure, the Scale for the Assessment and Rating of Ataxia (SARA), in longitudinal studies, and magnetic resonance spectroscopy (MRS) was shown to detect neurochemical abnormalities with high sensitivity cross-sectionally in SCA1. OBJECTIVES: The objectives of this study were to compare the sensitivities to change of volumetric MRI, MRS, and SARA in a 3-year longitudinal study in SCA1. METHODS: A total of 16 early-to-moderate stage patients with SCA1 (SARA 0-14) and 21 matched healthy participants were scanned up to 3 times with 1.5-year intervals. Ataxia severity was assessed with SARA. T1-weighted images and magnetic resonance spectra from the cerebellar vermis, cerebellar white matter, and pons were acquired at 3T. RESULTS: The pontine total N-acetylaspartate-to-myo-inositol ratio was the most sensitive MRS measure to change (-3.9 ± 4.6%/yr in SCA1 vs. -0.3 ± 3.5%/yr in controls; P < 0.02), and the pontine volume was the most sensitive MRI measure to change (-2.6 ± 1.2%/yr in SCA1 vs. -0.1 ± 1.2 in controls; P < 0.02). Effect size (mean percent change/standard deviation of percent change) of pontine volume was highest (-2.13) followed by pontine N-acetylaspartate-to-myo-inositol ratio (-0.84) and SARA (+0.60). The pontine N-acetylaspartate-to-myo-inositol ratio was abnormal for 1 premanifest patient at all visits and predicted study withdrawal as a result of disease progression in 3 patients. CONCLUSION: Both MRI and MRS were more sensitive to disease progression than SARA in SCA1. Pontine volume was most sensitive to change, whereas MRS may have more sensitivity at the premanifest stage and predictive value for disease progression.