Clinical features and immune-related protein patterns of anti-MDA5 positive clinically amyopathic dermatomyositis Dutch patients

OBJECTIVES: The presence of melanoma differentiation-associated protein 5 (MDA5) antibodies in patients with DM is associated with the development of a rapidly progressive interstitial lung disease (RPILD), unresponsive to conventional treatment. We characterize patients and provide more insight into potential biomarkers to identify patients with RPILD. METHODS: Patients diagnosed with anti-MDA5 positive DM between December 2015 and November 2017 were included in this study. Clinical data were retrospectively retrieved from medical records. A total of 180 immune-related markers were measured in sera of 16 patients and 15 healthy controls using proximity extension assay-based technology. RESULTS: Twenty patients were included, with a median time from symptoms till diagnosis of 4 months. All patients had clinically amyopathic DM. Interstitial lung disease (ILD) was present at diagnosis in 94% of the patients, 45% presented with RPILD. The mortality rate was 35% within 4 months after diagnosis and respiratory failure was the main cause of death in these patients. Furthermore, unsupervised analysis revealed that patients with RPILD show clearly different inflammatory serum profiles than healthy controls. In addition, in comparison to healthy controls, the IFN, IL1, IL10 and IL18 signalling pathways are different regulated in anti-MDA5 positive patients. CONCLUSION: In this Dutch anti-MDA5 positive clinically amyopathic DM (CADM) cohort, one-third of the patients died due to RPILD soon after diagnosis, which underlines the severity of this disease. In addition, we have found several possible pathways that are differentially regulated in RPILD vs no RPILD DM and healthy controls. These markers await further validation before clinical use

Genetic Variation in CCL18 Gene Influences CCL18 Expression and Correlates with Survival in Idiopathic Pulmonary Fibrosis: Part A

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease, characterized by fibroblast proliferation and extracellular matrix deposition. CC-chemokine ligand 18 (CCL18) upregulates the production of collagen by lung fibroblasts and is associated with mortality. This study was designed to evaluate the influence of single nucleotide polymorphisms (SNPs) in the CCL18 gene on CCL18 expression and survival in IPF. Serum CCL18 levels and four SNPs in the CCL18 gene were analyzed in 77 Dutch IPF patients and 349 healthy controls (HCs). CCL18 mRNA expression was analyzed in peripheral blood mononuclear cells (PBMCs) from 18 healthy subjects. Survival analysis was conducted, dependent on CCL18-levels and -genotypes and validated in two German IPF cohorts (Part B). IPF patients demonstrated significantly higher serum CCL18 levels than the healthy controls (p T genotype, with the highest CCL18-levels with the presence of the C-allele. Constitutive CCL18 mRNA-expression in PBMCs was significantly increased with the C-allele and correlated with serum CCL18-levels. In IPF, high serum levels correlated with decreased survival (p = 0.02). Survival was worse with the CT-genotype compared to the TT genotype (p = 0.01). Concluding, genetic variability in the CCL18-gene accounts for differences in CCL18 mRNA-expression and serum-levels and influences survival in IPF

Genetic Variation in CCL18 Gene Influences CCL18 Expression and Correlates with Survival in Idiopathic Pulmonary Fibrosis: Part A

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease, characterized by fibroblast proliferation and extracellular matrix deposition. CC-chemokine ligand 18 (CCL18) upregulates the production of collagen by lung fibroblasts and is associated with mortality. This study was designed to evaluate the influence of single nucleotide polymorphisms (SNPs) in the CCL18 gene on CCL18 expression and survival in IPF. Serum CCL18 levels and four SNPs in the CCL18 gene were analyzed in 77 Dutch IPF patients and 349 healthy controls (HCs). CCL18 mRNA expression was analyzed in peripheral blood mononuclear cells (PBMCs) from 18 healthy subjects. Survival analysis was conducted, dependent on CCL18-levels and -genotypes and validated in two German IPF cohorts (Part B). IPF patients demonstrated significantly higher serum CCL18 levels than the healthy controls (p T genotype, with the highest CCL18-levels with the presence of the C-allele. Constitutive CCL18 mRNA-expression in PBMCs was significantly increased with the C-allele and correlated with serum CCL18-levels. In IPF, high serum levels correlated with decreased survival (p = 0.02). Survival was worse with the CT-genotype compared to the TT genotype (p = 0.01). Concluding, genetic variability in the CCL18-gene accounts for differences in CCL18 mRNA-expression and serum-levels and influences survival in IPF