Tacrolimus personalized therapy based on CYP3A5 genotype in Chinese patients with idiopathic inflammatory myopathies.

OBJECTIVE: Idiopathic inflammatory myopathies (IIM) are a heterogeneous and life-threatening group of diseases; in particular, anti-melanoma differentiation-associated gene 5 antibody positive DM (MDA5+ DM) is reportedly strongly associated with high mortality rate. Tacrolimus (TAC) provides an excellent therapeutic option, but the trough concentration (Cmin)-outcome relationship remains unexplored. This study was undertaken to identify optimal Cmin and individualized dose based on CYP3A5 genotype for IIM patients. METHODS: A total of 134 IIM patients with 467 Cmin were enrolled. We examined the relationship between TAC Cmin and relapses. The receiver operating characteristic analysis was used to confirm the optimal Cmin. Analyses of factors influencing Cmin were conducted. The dose requirement based on CYP3A5 genotype was confirmed. RESULTS: TAC Cmin is strongly associated with relapses. The optimal cutoff values were 5.30, 5.85, 4.85 and 5.35 ng/ml for acute, subacute, chronic and all-phase IIM patients (P = 0.001, 0.013, 0.002 and <0.001, respectively), as well as 5.35, 5.85, 5.55 and 5.85 ng/ml for acute, subacute, chronic and all-phase MDA5+ DM patients (P = 0.007, 0.001, 0.036 and <0.001, respectively). CYP3A5 genotype was one of the significant factors influencing TAC Cmin. CYP3A5 expressers required 0.059 mg/kg/day to attain the target Cmin, while nonexpressers required 0.046 mg/kg/day (P = 0.019). CONCLUSION: TAC treatment may elicit favorable outcome in patients with IIM and MDA5+ DM when Cmin exceeded 5.35 and 5.85 ng/ml, which is crucial to a lower relapse rate. The individualized dose based on the CYP3A5 genotype provides a reference for TAC personalized therapy in IIM.

A nomogram based on clinical factors and CT radiomics for predicting anti-MDA5+ DM complicated by RP-ILD.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) DM complicated by rapidly progressive interstitial lung disease (RP-ILD) has a high incidence and poor prognosis. The objective of this study was to establish a model for the prediction and early diagnosis of anti-MDA5+ DM-associated RP-ILD based on clinical manifestations and imaging features. METHODS: A total of 103 patients with anti-MDA5+ DM were included. The patients were randomly split into training and testing sets of 72 and 31 patients, respectively. After image analysis, we collected clinical, imaging and radiomics features from each patient. Feature selection was performed first with the minimum redundancy and maximum relevance algorithm and then with the best subset selection method. The final remaining features comprised the radscore. A clinical model and imaging model were then constructed with the selected independent risk factors for the prediction of non-RP-ILD and RP-ILD. We also combined these models in different ways and compared their predictive abilities. A nomogram was also established. The predictive performances of the models were assessed based on receiver operating characteristics curves, calibration curves, discriminability and clinical utility. RESULTS: The analyses showed that two clinical factors, dyspnoea (P = 0.000) and duration of illness in months (P = 0.001), and three radiomics features (P = 0.001, 0.044 and 0.008, separately) were independent predictors of non-RP-ILD and RP-ILD. However, no imaging features were significantly different between the two groups. The radiomics model built with the three radiomics features performed worse than the clinical model and showed areas under the curve (AUCs) of 0.805 and 0.754 in the training and test sets, respectively. The clinical model demonstrated a good predictive ability for RP-ILD in MDA5+ DM patients, with an AUC, sensitivity, specificity and accuracy of 0.954, 0.931, 0.837 and 0.847 in the training set and 0.890, 0.875, 0.800 and 0.774 in the testing set, respectively. The combination model built with clinical and radiomics features performed slightly better than the clinical model, with an AUC, sensitivity, specificity and accuracy of 0.994, 0.966, 0.977 and 0.931 in the training set and 0.890, 0.812, 1.000 and 0.839 in the testing set, respectively. The calibration curve and decision curve analyses showed satisfactory consistency and clinical utility of the nomogram. CONCLUSION: Our results suggest that the combination model built with clinical and radiomics features could reliably predict the occurrence of RP-ILD in MDA5+ DM patients.

"Amyopathic" MDA5-positive dermatomyositis with severe lung involvement presenting with net myositic morphological features - insights from an autopsy study.

Anti-MDA5-positive dermatomyositis (MDA5-DM) often presents with extramuscular, especially pulmonary and skin manifestations, and apparent clinical signs of frank myositis can be missing (so called amyopathic DM). We hereby present two male patients who died from respiratory failure during the course of MDA5-DM. While overt signs of myositis or any skin involvement were absent at admission to hospital we noticed conspicuous inflammatory alterations in various skeletal muscles morphologically, showing different degrees of affection. Furthermore, pathological changes of the lungs compatible with rapid progressive interstitial lung disease and characteristic cutaneous vasculoocclusive features were identified at autopsy. This observation shows that muscles and skin are subclinically affected in a widespread fashion, hence subtle signs of muscle involvement should be sought after in anti-MDA5-positive patients with predominant lung affection to ensure adequate treatment.

Pathogenesis of Anti-melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis: A Concise Review With an Emphasis on Type I Interferon System.

Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis (MDA5+ DM) is typically characterized by cutaneous manifestations, amyopathic or hypomyopathic muscle involvement, and a high incidence of rapid progressive interstitial lung disease (RP-ILD). However, the exact etiology and pathogenesis of this condition has yet to be fully elucidated. Melanoma differentiation-associated gene 5 (MDA5), as the autoantigen target, is a member of the retinoic acid-inducible gene-I (RIG-I) family. The MDA5 protein can function as a cytosolic sensor that recognizes viral double-strand RNA and then triggers the transcription of genes encoding type I interferon (IFN). Therefore, it was presumed that viruses might trigger the overproduction of type I IFN, thus contributing to the development of MDA5+ DM. Emerging evidence provides further support to this hypothesis: the increased serum IFNα level was detected in the patients with MDA5+ DM, and the type I IFN gene signature was upregulated in both the peripheral blood mononuclear cells (PBMCs) and the skin tissues from these patients. In particular, RNA sequencing revealed the over-expression of the type I IFN genes in blood vessels from MDA5+ DM patients. In addition, Janus kinase (JAK) inhibitors achieved the promising therapeutic effects in cases with interstitial lung disease (ILD) associated with MDA5+ DM. In this review, we discuss the role of the type I IFN system in the pathogenesis of MDA5+ DM.