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• W4315607744 abstract "To the Editor: Dermatomyositis (DM) is an autoimmune connective tissue disease that typically presents with symmetrical proximal muscle weakness and a characteristic cutaneous eruption. However, clinical manifestations are protean, with some patients experiencing skin-limited disease while others develop serious systemic complications including interstitial lung disease (ILD). T-cell–mediated and humoral immune dysregulation have both been implicated in the pathogenesis of end-organ damage,1Zhang L. Wu G. Gao D. et al.Factors associated with interstitial lung disease in patients with polymyositis and dermatomyositis: a systematic review and meta-analysis.PLoS One. 2016; 11e0155381Google Scholar and autoantibodies such as anti-melanoma differentiation-associated gene 5 have emerged as important predictors of ILD.2Stuhlmüller B. Schneider U. González-González J.B. Feist E. Disease specific autoantibodies in idiopathic inflammatory myopathies.Front Neurol. 2019; 10: 438https://doi.org/10.3389/fneur.2019.00438Crossref PubMed Scopus (30) Google Scholar Despite these advances, our understanding of immunophenotypic prognostic factors associated with the development of ILD remains limited, and serum autoantibody profiles offer only modest accuracy for predicting end-organ disease.2Stuhlmüller B. Schneider U. González-González J.B. Feist E. Disease specific autoantibodies in idiopathic inflammatory myopathies.Front Neurol. 2019; 10: 438https://doi.org/10.3389/fneur.2019.00438Crossref PubMed Scopus (30) Google Scholar As such, alternative methods for DM patient stratification and prediction of ILD risk are needed. In this cohort study, we sought to identify biomarkers that might be differentially expressed in lesional skin obtained from patients with DM versus without ILD. After receiving institutional review board approval, we utilized NanoString technology to assess differential mRNA expression of 800 immune-related genes in formalin-fixed, paraffin-embedded lesional skin samples obtained from 5 patients with DM who developed radiographic evidence of ILD within 2 years of skin biopsy compared to 5 patients with DM who did not. Additional patient characteristics including serum autoantibody profiles are noted in Table I.Table IDemographic and clinical characteristics of dermatomyositis study cohortComorbid ILDNo (N = 5)Yes (N = 5)Age, mean (SD)34.2 (12.7)56.8 (19.5)Gender Male1 (20%)1 (20%) Female4 (80%)4 (80%)Race/ethnicity∗Race/ethnicity was classified by self-reporting as documented in the electronic medical record. Hispanic0 (0%)0 (0%) Black1 (20%)1 (20%) White2 (40%)3 (60%) Asian1 (20%)1 (20%) Pacific Islander or Native Hawaiian0 (0%)0 (0%) Unknown/not reported1 (20%)0 (0%)Dermatomyositis phenotype Clinically amyopathic (CADM)4 (80%)4 (80%) Myopathic (CDM)1 (20%)1 (20%) Cancer-associated myositis (CAM)0 (0%)0 (0%)Immunosuppressant therapy at time of skin biopsy2 (40%)1 (20%)Myositis-specific autoantibody MDA-51 (20%)3 (60%) TIF1-γ2 (40%)1 (20%) SUMO1 (20%)0 (0%) Mi-21 (20%)0 (0%) Jo-10 (0%)1 (20%)Evidence of ILD†Diagnosis of ILD made within 2 years of obtaining skin biopsy. PFTs with reduced lung volume and/or DLCO0 (0%)5 (100%) CT chest with radiographic features suggest of ILD0 (0%)5 (100%)CT, Computed tomography; DLCO, diffusion capacity for carbon monoxide; ILD, interstitial lung disease; MDA-5, anti-melanoma differentiation-associated gene; PFTs, pulmonary function tests; SUMO, anti-small ubiquitin-like modifier; TIF1-γ, anti-transcription intermediary factor 1.∗ Race/ethnicity was classified by self-reporting as documented in the electronic medical record.† Diagnosis of ILD made within 2 years of obtaining skin biopsy. Open table in a new tab CT, Computed tomography; DLCO, diffusion capacity for carbon monoxide; ILD, interstitial lung disease; MDA-5, anti-melanoma differentiation-associated gene; PFTs, pulmonary function tests; SUMO, anti-small ubiquitin-like modifier; TIF1-γ, anti-transcription intermediary factor 1. Among 42 highly regulated genes, 10 were significantly upregulated in patients with DM with ILD: CD44, NFKBIZ, CD24, EGR1, DEFB103B, CCL18, CCL22, CXCL2, S100A8, and S100A9 (Fig 1). Notably, serum levels of S100A8/A9 heterodimer an endogenous ligand of Toll-like receptor 4 correlate with clinical severity in patients with DM-associated ILD, thereby supporting NanoString’s utility in identifying salient genes associated with end-organ damage in DM.3Lou Y. Zheng Y. Fan B. et al.Serum levels of interleukins and S100A8/A9 correlate with clinical severity in patients with dermatomyositis-associated interstitial lung disease.BMC Pulm Med. 2020; 20: 196Crossref PubMed Scopus (10) Google Scholar,4Preusse C. Eede P. Heinzeling L. et al.NanoString technology distinguishes anti-TIF-1γ+ from anti-Mi-2+dermatomyositis patients.Brain Pathol. 2021; 31e12957Crossref PubMed Scopus (11) Google Scholar We also identified several novel genes downregulated in patients with DM-associated ILD that play a role in autophagy and adaptive immune activation: CLEC7, LEF1, KLRC2, BTLA, MUC1, and TCF7 (Fig 1).5Mehla K. Singh P.K. MUC1: a novel metabolic master regulator.Biochim Biophys Acta. 2014; 1845: 126-135PubMed Google Scholar To validate our findings, we performed immunohistochemical analysis, which confirmed increased expression of S100A9 and decreased expression of MUC1 in all 5 lesional skin samples obtained from patients with DM with ILD versus without ILD (Supplementary Fig 1, available via Mendeley at https://doi.org/10.17632/c6r473s3d2.1). Statistical analysis was performed using the unpaired 2-tailed t test with P < .05 indicating significance (Supplementary Methods, available via Mendeley at https://doi.org/10.17632/c6r473s3d2.1). Our results underscore the limitations of relying on serum autoantibody profiles to predict systemic disease in DM: one patient with ILD tested positive for anti-transcription intermediary factor 1-γ (TIF1-γ), an autoantibody more typically associated with malignancy-associated myositis,2Stuhlmüller B. Schneider U. González-González J.B. Feist E. Disease specific autoantibodies in idiopathic inflammatory myopathies.Front Neurol. 2019; 10: 438https://doi.org/10.3389/fneur.2019.00438Crossref PubMed Scopus (30) Google Scholar while another tested positive for anti-melanoma differentiation-associated gene 5 (MDA-5) and yet did not go on to develop ILD (Table I). As such, alternative methods for DM patient stratification and prediction of ILD risk are needed. Our findings begin to characterize an immune-related gene expression signature in lesional DM skin that may be associated with ILD development. Identification of biomarkers of systemic disease in lesional DM skin has the potential to more accurately risk stratify patients with DM at the time of tissue diagnosis and may even provide novel targets for early intervention against DM-associated ILD. Importantly, our study serves as an initial proof-of-principle experiment and will therefore require a larger, confirmatory cohort going forward to validate our findings. None disclosed." @default.
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• W4315607744 date "2023-05-01" @default.
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• W4315607744 title "Differential gene expression in lesional skin may signify immune-mediated lung parenchymal damage in patients with dermatomyositis" @default.
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• W4315607744 doi "https://doi.org/10.1016/j.jaad.2022.12.040" @default.
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