Dermatomyositis Skin Research Articles

Multiplexed Mass Cytometry of Cutaneous Lupus Erythematosus and Dermatomyositis Skin: An In-depth, B-Cell–Directed Immunoprofile

Multiplexed Mass Cytometry of Cutaneous Lupus Erythematosus and Dermatomyositis Skin: An In-depth, B-Cell–Directed Immunoprofile

Control of dermatomyositis skin disease activity lags behind control of muscles disease activity during the early treatment stages of classic dermatomyositis: A retrospective, single‐centre study

Control of dermatomyositis skin disease activity lags behind control of muscles disease activity during the early treatment stages of classic dermatomyositis: A retrospective, single‐centre study

Mitochondrial-related hub genes in dermatomyositis: muscle and skin datasets-based identification and in vivo validation.

Background: Mitochondrial dysfunction has been implicated in the pathogenesis of dermatomyositis (DM), a rare autoimmune disease affecting the skin and muscles. However, the genetic basis underlying dysfunctional mitochondria and the development of DM remains incomplete. Methods: The datasets of DM muscle and skin tissues were retrieved from the Gene Expression Omnibus database. The mitochondrial related genes (MRGs) were retrieved from MitoCarta. DM-related modules in muscle and skin tissues were identified with the analysis of weighted gene co-expression network (WGCNA), and then compared with the MRGs to obtain the overlapping mitochondrial related module genes (mito-MGs). Subsequently, differential expression genes (DEGs) obtained from muscle and skin datasets were overlapped with MRGs to identify mitochondrial related DEGs (mito-DEGs). Next, functional enrichment analysis was applied to analyze possible relevant biological pathways. We used the Jvenn online tool to intersect mito-MGs with mito-DEGs to identify hub genes and validate them using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry staining. In addition, we evaluated immune infiltration in muscle and skin tissues of DM patients using the one-sample gene set enrichment analysis (ssGSEA) algorithm and predicted potential transcription factor (TF) -gene network by NetworkAnalyst. Results: The WGCNA analysis revealed 105 mito-MGs, while the DEG analysis identified 3 mito-DEGs. These genes showed functional enrichment for amino acid metabolism, energy metabolism and oxidative phosphorylation. Through the intersection analysis of the mito-MGs from the WGCNA analysis and the mito-DEGs from the DEG set, three DM mito-hub genes (IFI27, CMPK2, and LAP3) were identified and validated by RT-qPCR and immunohistochemistry analysis. Additionally, positive correlations were observed between hub genes and immune cell abundance. The TF-hub gene regulatory network revealed significant interactions involving ERG, VDR, and ZFX with CMPK2 and LAP3, as well as SOX2 with LAP3 and IFI27, and AR with IFI27 and CMPK2. Conclusion: The mito-hub genes (IFI27, CMPK2, and LAP3) are identified in both muscles and skin tissues from DM patients. These genes may be associated with immune infiltration in DM, providing a new entry point for the pathogenesis of DM.

Validation of Cutaneous Dermatomyositis Disease Area and Severity Index Activity Score and Other Efficacy Outcomes as Measures of Skin Disease in Dermatomyositis in the Lenabasum Phase 3 Trial

In the past decade, there have been six industry-sponsored phase 3 trials in adult patients with dermatomyositis (DM), primarily focusing on improving muscle weakness. However, skin disease is a cardinal manifestation of DM. This study evaluated the sensitivity of Cutaneous Dermatomyositis Disease Area and Severity Index Activity score, Cutaneous Dermatomyositis Activity Investigator Global Assessment, Total Improvement Score, and other outcome measures used in DM clinical trials to detect improvement in DM skin disease activity. Data analyzed from the lenabasum phase 3 trial in DM showed that improvement in Cutaneous Dermatomyositis Disease Area and Severity Index Activity score increased proportionately with the degree of patient- or physician-reported improvement in skin disease, consistently measuring improvement when clinically meaningful improvement was reported at weeks 16-52. In contrast, Cutaneous Dermatomyositis Activity Investigator Global Assessment measured little change from baseline with reported no improvement in skin disease but also a similar change from baseline with slight improvement. No Skindex-29+3 subscale performed well at reflecting increasing degrees of improvement in skin disease. Extramuscular Global Assessment and Total Improvement Score generally showed increasing levels of improvement as the degree of patient- and physician-reported improvement in skin disease increased, but these are composite measures and are not specific to improvement in DM skin disease. To measure clinically meaningful improvement in skin disease in a DM trial, Cutaneous Dermatomyositis Disease Area and Severity Index Activity score is the more sensitive outcome measure across time points.

Pruritogenic molecules in the skin of patients with dermatomyositis.

Pruritus is a common excruciating symptom in systemic autoimmune diseases such as dermatomyositis (DM) but the pathogenesis is not fully understood. We intended to investigate the targeted expression analysis of candidate molecules involved in the development of pruritus in lesional vs. non-lesional skin samples of patients affected with active DM. We looked for correlations between the investigated pruriceptive signaling molecules, disease activity, and itching sensation of DM patients. Interleukins (IL-33 and IL-6), tumor necrosis factor α (TNF-α), peroxisome proliferator-activated receptor γ (PPAR-γ), and ion channels belonging to the transient receptor potential (TRP) family were analyzed. The expression of TNF-α, PPAR-γ, IL-33, IL-6, and TRP channels in lesional DM skin was evaluated by RT-qPCR and immunohistochemistry and was compared with non-lesional DM skin samples. Pruritus, disease activity, and damage of DM were evaluated by the 5-D itch scale and Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), respectively. Statistical analysis was performed with IBM SPSS 28 software. A total of 17 active DM patients participated in the study. We could show that the itching score was positively correlated with the CDASI activity score (Kendall's tau-b = 0.571; p = 0.003). TNF-α gene expression was significantly higher in lesional DM skin than in non-lesional DM skin (p = 0.009) and differed in the subgroups of patients with different itch intensities (p = 0.038). The mRNA expression of lesional IL-6 correlated positively with 5-D itch and CDASI activity score (Kendall's tau-b = 0.585; p = 0.008 and 0.45; p = 0.013, respectively). TRPV4 expressions were positively correlated with CDASI damage score (Kendall's tau-b = 0.626; p < 0.001), but the mRNA expressions of the TRP family, PPAR-γ, IL-6, and IL-33 were not different in lesional and non-lesional samples. Immunohistochemistry analysis did not find significant alterations in the expressions of TNF-α, PPAR-γ, IL-6, and IL-33 in lesional and non-lesional regions. Our results argue that cutaneous disease activity, TNF-α, and IL-6 might play a central role in DM-associated itch, while TRPV4 plays a central role in tissue regeneration.

133 UVB-induced type-I interferon in keratinocytes is associated with expansion of CXCL13+ skin-resident memory T cells in dermatomyositis skin

133 UVB-induced type-I interferon in keratinocytes is associated with expansion of CXCL13+ skin-resident memory T cells in dermatomyositis skin

Dermatomyositis autoantigen CHD4 forms immune stimulatory complexes with endogenous DNA.

Dermatomyositis (DM) is an idiopathic inflammatory myopathy belonging to the spectrum of autoimmune connective tissue diseases. DM patients present with antinuclear antibodies against Mi-2, also known as Chromodomain-helicase-DNA-binding protein 4 (CHD4). CHD4 is upregulated in DM skin biopsies and could potentially affect DM pathophysiology as it binds endogenous DNA with a high affinity (KD = 0.2 nM ± 0.076 nM) and forms CHD4-DNA complexes. The complexes are localized in the cytoplasm of UV-radiated and transfected HaCaTs and amplify the expression of interferon (IFN) regulated genes and the amount of functional CXCL10 protein stronger than DNA alone. The enhancement of the type I IFN pathway activation in HaCaTs through CHD4-DNA signalling suggests a possible mechanism for the sustainment of the pro-inflammatory vicious cycle in DM skin lesions.

Amyopathic Dermatomyositis Manifesting With Marked Unilateral Eyelid Swelling and Hyperpigmentation in a Darker Skin Tone

A 56-year-old man presented to the emergency department with unilateral eyelid swelling, a hyperpigmented rash, and no myositis. His physical examination showcases the variable presentation of classic dermatomyositis skin manifestations in darker skin. Dermatomyositis is an uncommon disease characterized by proximal muscle weakness and classic dermatologic manifestations. In amyopathic disease, the diagnosis relies on the identification of dermatologic findings, in which variation in manifestations can lead to delays in diagnosis and increased health disparities.

Imaging Mass Cytometry Reveals Predominant Innate Immune Signature and Endothelial-Immune Cell Interaction in Juvenile Myositis Compared to Lupus Skin.

Cutaneous inflammation can signal disease in juvenile dermatomyositis (DM) and childhood-onset systemic lupus erythematosus (cSLE), but we do not fully understand cellular mechanisms of cutaneous inflammation. In this study, we used imaging mass cytometry to characterize cutaneous inflammatory cell populations and cell-cell interactions in juvenile DM as compared to cSLE. We performed imaging mass cytometry analysis on skin biopsy samples from juvenile DM patients (n=6) and cSLE patients (n=4). Tissue slides were processed and incubated with metal-tagged antibodies for CD14, CD15, CD16, CD56, CD68, CD11c, HLA-DR, blood dendritic cell antigen 2, CD20, CD27, CD138, CD4, CD8, E-cadherin, CD31, pan-keratin, and type I collagen. Stained tissue was ablated, and raw data were acquired using the Hyperion imaging system. We utilized the Phenograph unsupervised clustering algorithm to determine cell marker expression and permutation test by histoCAT to perform neighborhood analysis. We identified 14 cell populations in juvenile DM and cSLE skin, including CD14+ and CD68+ macrophages, myeloid and plasmacytoid dendritic cells (pDCs), CD4+ and CD8+ T cells, and B cells. Overall, cSLE skin had a higher inflammatory cell infiltrate, with increased CD14+ macrophages, pDCs, and CD8+ T cells and immune cell-immune cell interactions. Juvenile DM skin displayed a stronger innate immune signature, with a higher overall percentage of CD14+ macrophages and prominent endothelial cell-immune cell interaction. Our findings identify immune cell population differences, including CD14+ macrophages, pDCs, and CD8+ T cells, in juvenile DM skin compared to cSLE skin, and highlight a predominant innate immune signature and endothelial cell-immune cell interaction in juvenile DM, providing insight into candidate cell populations and interactions to better understand disease-specific pathophysiology.

021 CXCL13-producing peripheral T helper cells as potential mediators of photosensitivity in dermatomyositis

Dermatomyositis (DM) is a rare autoimmune disease that causes photosensitivity, disfiguring rash, and pruritus. Type I interferons (IFN-Is) are expressed in lesional (L) skin of DM, suggesting their role in disease pathogenesis. Using suction blistering on both L and non-lesional (NL) skin of treatment-naïve patients with DM followed by single-cell RNA sequencing (scRNA-seq) and flow cytometry, we found a distinct population of T cells expressing high levels of CXCL13, only in L DM. Their immunophenotype (CD4+/PD-1hi/CXCR5-) was characteristic of T peripheral helper (Tph) cells, a new subset of T cells recently described to drive autoimmunity in rheumatoid arthritis via CXCL13 mediated recruitment of B cells to synovium. However, consistent with previous reports, we did not find any B cells infiltrating L DM skin. Intriguingly, we observed high expression of CXCR5 on a subset of CD8+ T cells in both DM blood and L skin, suggesting CXCL13 promotes recruitment of cytotoxic CD8+ T cells to the inflamed skin. ELISA on the interstitial skin fluid confirmed higher levels of CXCL13 in L DM than NL and healthy (p<0.001), and immunohistochemistry highlighted CXCL13 staining colocalizing within perivascular CD4+ T cells. Using gene set enrichment analysis in our scRNA-seq data, we identified a robust IFN-I signature in Tph cells in DM skin. Further, we found that CD4+ T cells from DM blood displayed a significantly higher CXCL13 expression in response to IFNA than those from healthy subjects in vitro (p<0.01). Moreover, we observed that keratinocytes (KCs) isolated from L DM exhibit an enhanced IFNA expression in response to UVB than healthy in vitro, indicating an exaggerated IFN-I response to UVB in DM KCs induces differentiation of CXCL13-producing Tph cells in the skin, leading to the recruitment of circulating cytotoxic CD8+ T cells. These findings suggest a novel role for the IFN-I/CXCL13 axis in DM pathogenesis and its potential contribution to photosensitivity.

023 Lenabasum, a cannabinoid type 2 receptor agonist, exerts anti-inflammatory effects in dermatomyositis in Th1 cells

Dermatomyositis (DM) is a chronic, systemic autoimmune disease affecting the skin, muscle, and lungs. Lenabasum, a non-psychoactive cannabinoid type 2 receptor (CB2R) agonist, is currently being investigated as a non-immunosuppressive treatment option for DM. The activation of CB2R has been shown to reduce several key pro-inflammatory cytokines implicated in DM. Our lab has previously demonstrated via immunohistochemistry (IHC) that Lenabasum decreases CD4, IFNβ, IFNγ and IL31 expression in DM skin at 12 weeks (p<0.05), with no differences in IL4 compared to placebo (p>0.05). In this study, we then utilized multiplexed flow cytometry of leukocytes eluted from DM skin to further analyze the expression of CB2R on 12 cell lineages. When evaluating cell lineages, CD4 T helper (Th) subsets were gated on CD4+ IFNγ+ Th1 and CD4+IL4+ Th2. There was a significantly higher frequency of parent (FOP) percentage (p<0.05) of CB2R in Th1 (61.05%, n=6) versus Th2 cells (25.5%, n=6). Among myeloid cell lineages, there was greater FOP of CB2R in M2 macrophages (CD68+CD163+), CD14++CD16++ macrophages, and monocyte derived dendritic cells (moDCs; CD11c+CD14+). With 15mmol of Lenabasum, there was a trend towards a decrease of: TNFα in M2 macrophages; IFNγ and IFNβ in CD4+ Tcells; IFNβ in CD16+ cells; and IL31 in Th1 cells, CD14++CD16+ macrophages, and M2 macrophages. There was also a significant decrease in moDCs secreting IL31 with Lenabasum (p<0.01). Imaging mass cytometry of untreated DM skin demonstrated the highest IL31 MPI in moDCs. IL31 was also elevated to a lesser extent in other myeloid cell lineages. These data suggest Lenabasum may exert specific anti-inflammatory effects in DM, particularly on Th1 cells and Th1-derived IL31.

068 Lenabasum reduces IFNγ and pIRF3 in dermatomyositis skin: Biomarker results from a double-blind phase 3 international randomized controlled trial

Dermatomyositis is an autoimmune skin disease with limited treatment options, and lenabasum is a cannabinoid type 2 receptor agonist with anti-inflammatory properties. Our previous work showed that IFNg and IL31 are increased in DM skin vs. skin from healthy controls and lenabasum reduces type 1 interferon (IFN-1) and IL-31 production by DM PBMCs in vitro. Lenabasum 20 mg BID treatment improved CDASI activity (CDASI-A) scores vs. placebo at 1 year in an international, double-blind, randomized Phase 3 trial.

039 Single-cell RNA-sequencing captures the cellular diversity within lesional and non-lesional skin of patients with dermatomyositis

Dermatomyositis (DM) is a devastating and poorly understood autoimmune disease characterized by prominent muscle weakness and relapsing refractory skin rashes. To investigate the cellular composition and comprehensive transcriptional effects of DM, we analyzed lesional and sun-protected, non-lesional skin from 8 patients with active cutaneous DM using scRNA-seq. Samples were analyzed in parallel with skin from 8 sex-matched healthy controls. Clustering and annotation revealed 12 major cell types, with prominent disease-associated shifts observed in both stromal and immune cell populations in DM skin.

The Utility of Myositis Specific Antibodies in Clinical Practice.

Fifteen myositis-specific antibodies have been described and characterized over the past 40 years. Approximately two thirds of patients with idiopathic inflammatory myositis have a myositis-specific antibody and only rarely more than one. Assays to detect them are now widely available within clinical practice. We describe the original description and clinical phenotype of the myositis-specific antibodies, forming the antisynthetase syndrome group, anti-MDA-5 and rapidly progressive interstitial lung disease, anti-SRP/HMGCR and necrotizing myositis, anti-TIF-1γ/NXP-2 and malignancy, anti-SAE and esophageal disease, and anti-Mi-2 and classic dermatomyositis skin disease. Clinical practice is likely to be refined, with diagnosis and classification of the idiopathic inflammatory myositides based primarily on myositis-specific antibody, rather than directed by muscle histology or the broader clinical characteristics of polymyositis and dermatomyositis. All patients newly presenting with idiopathic inflammatory myositis should be routinely screened for myositis-specific antibodies. A positive result will usefully provide diagnostic and prognostic information, guide selection of therapy, and prompt surveillance for potential organ involvement and other features, such as cancer, throughout the disease course.

Systemic Sclerosis-Specific Antibodies: Novel and Classical Biomarkers

Disease-specific autoantibodies are considered the most important biomarkers for systemic sclerosis (SSc), due to their ability to stratify patients with different severity and prognosis. Anti-nuclear antibodies (ANA), occurring in subjects with isolated Raynuad’s phenomenon, are considered the strongest independent predictors of definite SSc and digital microvascular damage, as observed by nailfold videocapillaroscopy. ANA are present in more than 90% of SSc, but ANA negativity does not exclude SSc diagnosis: a little rate of SSc ANA negative exists and shows a distinct subtype of disease, with less vasculopathy, but more frequent lower gastrointestinal involvement and severe disease course. Anti-centromere, anti-Th/To, and anti-Topoisomerase I antibodies could be considered as classical biomarkers, covering about 60% of SSc and defining patients with well-described cardio-pulmonary complications. In particular, anti-Topoisomerase I represent a risk factor for development of diffuse cutaneous involvement and digital ulcers in the first 3 years of disease, as well as severe interstitial lung disease (ILD). Anti-RNA polymerase III is a biomarker with new clinical implications: very rapid skin thickness progression, gastric antral vascular ectasia, the occurrence of synchronous cancers, and possible association with silicone breast implants rupture. Moreover, novel SSc specific autoantibodies have been globally described in about 10% of “seronegative” SSc patients: anti-elF2B, anti-RuvBL1/2 complex, anti-U11/U12 RNP, and anti-BICD2 depict specific SSc subtypes with severe organ complications. Many autoantibodies could be considered markers of overlap syndromes, including SSc. Anti-Ku are found in 2–7% of SSc, strictly defining the PM/SSc overlap. They are associated with synovitis, joint contractures, myositis, and negatively associated with vascular manifestation of disease. Anti-U3RNP are associated with a well-defined clinical phenotype: Afro-Caribbean male patients, younger at diagnosis, and higher risk of pulmonary hypertension and gastrointestinal involvement. Anti-PM/Scl define SSc patients with high frequency of ILD, calcinosis, dermatomyositis skin changes, and severe myositis. The accurate detection of autoantibodies SSc specific and associated with overlap syndromes is crucial for patients’ stratification. ANA should be correctly identified using indirect immunofluorescent assay and a standardized way of patterns’ interpretation. The gold-standard technique for autoantibodies’ identification in SSc is still considered immunoprecipitation, for its high sensitivity and specificity, but other assays have been widely used in routine practice. The identification of SSc autoantibodies with high diagnostic specificity and high predictive value is mandatory for early diagnosis, a specific follow-up and the possible definition of the best therapy for every SSc subsets. In addition, the validation of novel autoantibodies is mandatory in wider cohorts in order to restrict the gap of so-called seronegative SSc patients.

Safety and Efficacy of Lenabasum, a Cannabinoid Receptor Type 2 Agonist, in Patients with Dermatomyositis with Refractory Skin Disease: A Randomized Clinical Trial

Treatment options are limited for skin disease in dermatomyositis. Lenabasum is a cannabinoid receptor type 2 agonist that triggers the resolution of inflammation. The objective of this study was to evaluate the safety and efficacy of lenabasum in patients with refractory cutaneous dermatomyositis. This study was a single-center, double-blind, randomized, placebo-controlled phase 2 study conducted from July 2015 to August2017. The population included subjects aged ≥18 years with at least moderately active dermatomyositis skin activity by Cutaneous Dermatomyositis Disease Area and Severity Index activity ≥ 14 and failure or intolerance to hydroxychloroquine. Participants received 20 mg lenabasum daily for 28 days and then 20 mg twice per day for 56 days or placebo. The primary outcome was a change in Cutaneous Dermatomyositis Disease Area and Severity Index activity. Safety and other secondary efficacy assessments were performed till day113. A total of 22 subjects were randomized to lenabasum (n= 11) or placebo (n= 11). No serious or severe adverse events were related to lenabasum, and no participants discontinued the study. The adjusted least-squares mean for Cutaneous Dermatomyositis Disease Area and Severity Index activity decreased more for lenabasum, and the difference was significant on day 113 (least-squares mean [standard error] difference= ‒6.5 [3.1], P= 0.038). Numerically greater improvements were seen in multiple secondary efficacy outcomes and biomarkers with lenabasum. Lenabasum treatment was well tolerated and was associated with greater improvement in Cutaneous Dermatomyositis Disease Area and Severity Index activity and multiple efficacy outcomes. This study was registered at ClinicalTrials.gov, NCT02466243.

P222 Clinical features of extra-muscular disease in dermatomyositis and anti-synthetase syndrome patients with skin involvement classified by presence of disease-specific autoantibodies: results from the EuroMyositis registry

Abstract Background/Aims Anti-synthetase syndrome (ASS) represents a distinct entity within myositis spectrum disorders; however, correct classification of patients with anti-tRNA synthetase autoantibodies and skin manifestations akin to dermatomyositis (DM) remains uncertain. Our aim was to compare clinical characteristics, skin involvement, and malignancy, between patients with ASS and DM, classified by disease-specific autoantibodies. Methods Data from 05/2009-03/2016 from 9 countries from the prospective, myositis EuroMyositis registry were downloaded. Those with anti-tRNA synthetase autoantibodies (Jo-1/PL-7/PL-12/OJ/EJ/KS) were classified as ASS, and those with Mi-2/TIF1-γ/NXP2/SAE/MDA5 autoantibodies as DM. Clinical phenotypes including malignancies (except skin malignancies) were tabulated. Characteristics of patients with skin involvement (excluding mechanic’s hands and Raynaud’s phenomenon) were compared using Fisher’s exact test with Bonferroni corrected p-values. Results Of 3,067 patients, 2,028 had autoantibody profiling results (66.1%), of which 783 (38.6%) were positive for at least one of the autoantibodies being considered. Five patients with dual autoantibody specificities were excluded. Of the remaining 778, 320 (41.1%) were classified as DM, and 458 (58.9%) as ASS. Median age at diagnosis was 48.2 years (interquartile range [IQR] 37.5 to 57.8) in the DM cohort and 49 (IQR 38.3 to 62.2) in the ASS cohort. Skin involvement was present in 277 (86.6%) DM patients (DM skin) vs 204 (44.5%) ASS patients (ASS skin) (pcorr&amp;lt;0.01) (Table 1). Whilst relatively high proportions of so-called “DM-specific” rashes were seen in ASS skin, the frequency of heliotrope rash, Gottron’s papules, violaceous rash, periorbital rash, V-sign, shawl sign, and periungual erythema was significantly higher in DM skin (pcorr&amp;lt;0.01 for all). Conversely, mechanic’s hands, Raynaud’s, arthritis, and interstitial lung disease were more frequent in ASS skin (pcorr&amp;lt;0.01 for all). Malignancy was less frequent in ASS skin vs DM skin (pcorr&amp;lt;0.01) and occurred temporally closer to myositis diagnosis in DM skin (median 0.95 months [IQR -6.54. to 19.45]) vs ASS skin (median 12.17 months [IQR -15.85 to 79.31]). Conclusion Patients with ASS have frequent skin involvement but also a distinct clinical phenotype compared to DM. These findings may inform the development of future classification criteria for ASS. Disclosure R.M. Hum: None. J.B. Lilleker: None. J.A. Lamb: None. W.E. Ollier: None. G. Wang: None. L.R. Wedderburn: None. L.P. Diederichsen: None. J. Schmidt: None. P. Oakley: None. O. Benveniste: None. M.G. Danieli: None. K. Danko: None. N.T.P. Thuy: None. M.V.D. Mercado: None. H. Andersson: None. B.D. Paepe: None. J.L.D. Bleecker: None. B. Maurer: None. L.J. McCann: None. N. Pipitone: None. N. McHugh: None. P. New: None. J. Vencovsky: None. I.E. Lundberg: None. H. Chinoy: None.

Update on Cutaneous Signs to Assist in the Diagnosis of Dermatomyositis.

Dermatomyositis (DM) is a heterogeneous idiopathic inflammatory myopathy that can be challenging to diagnose. Learning about the cutaneous manifestations in DM can assist with prompt diagnosis as well as subgroup classification. This review highlights recent data regarding cutaneous signs in DM and their associations with myositis-specific antibodies (MSAs). Several novel DM skin signs have recently been reported. Novel and confirmatory data have helped to define more clearly the associations between various cutaneous manifestations and MSAs. Awareness of the diverse cutaneous phenotypes can help with the timely diagnosis of DM. As some MSAs are associated with atypical skin features and/or characteristic patterns of clinical findings, knowledge of these associations can help clinicians to recognize DM patients. Understanding how the prevalence and presentation of various cutaneous signs differ among ethnically diverse patients is a high priority for further study.

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

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. 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). IF staining for MxA and IFNβ 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 IFNβ (P < 0.001). 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.

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

BackgroundLenabasum 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.MethodsImmunohistochemistry 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.ResultsAfter 12 weeks of lenabasum treatment, IHC staining showed that CD4+ T cells, CB2R, IL-31, IFN-γ, and IFN-β cytokines were downregulated. IFN-γ and IFN-β 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-β.ConclusionOur 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.