Interstitial Lung Disease in Anti-MDA5 Positive Dermatomyositis

Wu, Wanlong; Guo, Li; Fu, Yanbin; Wang, Kaiwen; Zhang, Danting; Xu, Wenwen; Chen, Zhiwei; Ye, Shuang

doi:10.1007/s12016-020-08822-5

Cited by 131 publications

(135 citation statements)

References 72 publications

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“…Anti-melanoma differentiation-associated gene 5 (MDA5) antibody is considered a specific serological marker in dermatomyositis (DM), which is typically linked to the amyopathic phenotype and rapidly progressive interstitial lung disease (ILD) (1). The pathogenesis of anti-MDA5 antibodypositive (anti-MDA5 + ) DM is largely unknown; however, possible genetic factors (with East Asian predisposition) and environmental triggers (such as viral infection) have been implicated (2). MDA5, encoded by the IFIH1 gene, is the key sensor of viral double-strand RNA (dsRNA) and belongs to the retinoic acid-induced gene I (RIG-I)-like receptors (3), which are actively involved in the type I interferon (IFN-a and IFN-b) pathway.…”

Section: Introductionmentioning

confidence: 99%

RNA-Containing Immune Complexes Formed by Anti-Melanoma Differentiation Associated Gene 5 Autoantibody Are Potent Inducers of IFN-α

Wang

Zhao

et al. 2021

Front. Immunol.

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ObjectiveAnti-melanoma differentiation-associated gene 5 (MDA5) autoantibody is a distinctive serology hallmark of dermatomyositis (DM). As an autoantigen, MDA5 is a cytoplasmic RNA recognition receptor. The aim of this study was to address the question of whether the RNA-containing immune complex (IC) formed by MDA5 and anti-MDA5 could activate type I interferon (IFN) response.MethodPatients with anti-MDA5+ DM (n = 217), anti-MDA5− DM (n = 68), anti-synthase syndrome (ASyS, n = 57), systemic lupus erythematosus (SLE, n = 245), rheumatoid arthritis (RA, n = 89), and systemic sclerosis (SSc, n = 30) and healthy donors (HD, n = 94) were enrolled in our studies. Anti-MDA5 antibody was detected by line blotting, enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, and Western blotting. Cytokine profiling was determined by multiplex flow cytometry, and IFN-α was further measured by ELISA. Type I IFN-inducible genes were detected by quantitative PCR (qPCR). RNA–IC binding was analyzed by RNA immunoprecipitation. Plasmacytoid dendritic cells (pDCs) derived from healthy donors were cultivated and stimulated with MDA5 ICs with or without RNase and Toll-like receptor 7 (TLR-7) agonist. The interaction between MDA5 ICs and TLR7 was evaluated by immunoprecipitation and confocal microscopy.ResultsAccording to our in-house ELISA, the presence of anti-MDA5 antibody in 76.1% of DM patients, along with 14.3% of SLE patients who had a lower titer yet positive anti-MDA5 antibody, was related to the high level of peripheral IFN-α. ICs formed by MDA5 and anti-MDA5 were potent inducers of IFN-α via TLR-7 in an RNA-dependent manner in vitro.ConclusionOur data provided evidence of the mechanistic relevance between the anti-MDA5 antibody and type I IFN pathway.

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Section: Introductionmentioning

confidence: 99%

RNA-Containing Immune Complexes Formed by Anti-Melanoma Differentiation Associated Gene 5 Autoantibody Are Potent Inducers of IFN-α

Wang

Zhao

et al. 2021

Front. Immunol.

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“…The overall prognosis of MDA5 + DM-ILD is poor with most fatalities occurring within the first half year since disease onset. A gravely 6-month mortality rate of around 50% was reported despite the intensive immunosuppressive therapy (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

A Computed Tomography Radiomics-Based Prediction Model on Interstitial Lung Disease in Anti-MDA5-Positive Dermatomyositis

Zheng³

et al. 2021

Front. Med.

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Objectives: Anti-melanoma differentiation-associated gene 5-positive dermatomyositis-associated interstitial lung disease (MDA5+ DM-ILD) is a life-threatening disease. The current study aimed to quantitatively assess the pulmonary high-resolution computed tomography (HRCT) images of MDA5+ DM-ILD by applying the radiomics approach and establish a multidimensional risk prediction model for the 6-month mortality.Methods: This retrospective study was conducted in 228 patients from two centers, namely, a derivation cohort and a longitudinal internal validation cohort in Renji Hospital, as well as an external validation cohort in Guangzhou. The derivation cohort was randomly divided into training and testing sets. The primary outcome was 6-month all-cause mortality since the time of admission. Baseline pulmonary HRCT images were quantitatively analyzed by radiomics approach, and a radiomic score (Rad-score) was generated. Clinical predictors selected by univariable Cox regression were further incorporated with the Rad-score, to enhance the prediction performance of the final model (Rad-score plus model). In parallel, an idiopathic pulmonary fibrosis (IPF)-based visual CT score and ILD-GAP score were calculated as comparators.Results: The Rad-score was significantly associated with the 6-month mortality, outperformed the traditional visual score and ILD-GAP score. The Rad-score plus model was successfully developed to predict the 6-month mortality, with C-index values of 0.88 [95% confidence interval (CI), 0.79–0.96] in the training set (n = 121), 0.88 (95%CI, 0.71–1.0) in the testing set (n = 31), 0.83 (95%CI, 0.68–0.98) in the internal validation cohort (n = 44), and 0.84 (95%CI, 0.64–1.0) in the external validation cohort (n = 32).Conclusions: The radiomic feature was an independent and reliable prognostic predictor for MDA5+ DM-ILD.

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“…It is widely known that the short-term prognosis of MDA5 + DM-ILD patients is poor (18). Accurate prediction of MDA5 + DM patient outcomes is a key issue in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

The Value of Effective Lung Ventilation Area Ratio Based on CT Image Analysis Is a New Index to Predict the Shorter Outcome of Anti-melanoma Differentiation-Associated Protein 5 Positive Dermatomyositis Associated Interstitial Lung Disease: A Single-Center Retrospective Study

Wang

Mei

et al. 2021

Front. Med.

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Background: Anti-melanoma differentiation-associated protein 5 (MDA5) positive dermatomyositis (MDA5+DM) patients have poor outcomes due to rapidly progressive interstitial lung disease (ILD). The accurate assessment of lung involvement is an urgent focus of research.Methods: A computer-aided lung interstitial image analysis technology has been developed, and a quantitative indicator named effective lung ventilation area ratio (ELVAR) that calculates the proportion of the area outside the lung interstitium in lung tissue has been established. 55 newly diagnosed MDA5+DM patients and 46 healthy individuals, matched for age and gender, were enrolled in this study. MDA5+DM patients were classified into early death group or early survival group according to their survival state within 3 months after diagnosis. Clinical characteristics, laboratory and immunological test results, lung involvement (including ELVAR value) and treatment were compared between early death group and early survival group to determine an index that can predict prognoses of patients with MDA5+DM.Results: There were significant differences between early death MDA5+DM patients and early survival MDA5+DM patients about 12 indices including age of onset, CRP, ferritin, albumin, and pulmonary involvement including severity of type I respiratory failure at diagnosis, P/F ratio, oxygen supplementation, values of ELVAR, FVC, and DLCO. The results of ROC analysis and correlation analysis showed the value of ELVAR had good diagnostic value and widely correlation with many clinical characteristics. Univariate analysis and Multivariate analysis showed four factors including age of onset, ferritin, value of ELVAR, and oxygen supplementation >4 L/min significantly value for poor prognosis in MDA5+DM patients. A cutoff value of 0.835 about ELVAR had good predictive power for mortality within 3 months in 54.2% of MDA5+DM patients.Conclusion: The value of ELVAR derived from computed tomography image analysis is a new index that can predict poor outcomes in MDA5+DM patients with rapidly progressive interstitial lung disease.

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Interstitial Lung Disease in Anti-MDA5 Positive Dermatomyositis

Cited by 131 publications

References 72 publications

RNA-Containing Immune Complexes Formed by Anti-Melanoma Differentiation Associated Gene 5 Autoantibody Are Potent Inducers of IFN-α

RNA-Containing Immune Complexes Formed by Anti-Melanoma Differentiation Associated Gene 5 Autoantibody Are Potent Inducers of IFN-α

A Computed Tomography Radiomics-Based Prediction Model on Interstitial Lung Disease in Anti-MDA5-Positive Dermatomyositis

The Value of Effective Lung Ventilation Area Ratio Based on CT Image Analysis Is a New Index to Predict the Shorter Outcome of Anti-melanoma Differentiation-Associated Protein 5 Positive Dermatomyositis Associated Interstitial Lung Disease: A Single-Center Retrospective Study

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