Background/Purpose: Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5+ DM) is an autoimmune condition associated with rapidly progressive interstitial lung disease (RP-ILD) and high mortality. Metabolic disturbances have been reported in inflammatory myopathies, including DM. However, whether alterations of metabolomics profiling participate in ILD development in MDA5+ DM remains undetermined.

Methods: Untargeted and targeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LC-MS) to profile metabolites in distinct subtypes of MDA5+ DM patients (RP-ILD, n = 25, C-ILD, n = 25, non-ILD, n = 24) and healthy controls (HCs, n = 41). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to identify altered pathways. Pearson correlation analysis was employed to investigate the correlation between metabolites and clinical/laboratory continuous variables.

Results: The metabolic imbalance observed in the plasma of MDA5+ DM patients predominantly affects amino acid metabolism. Compared to MDA5+ DM patients with chronic ILD, non-ILD, and HCs, MDA5+ DM patients with RP-ILD exhibited significant alterations in tryptophan (TRP) and its metabolites (RP-ILD vs C-ILD: P = 0.0006, RP-ILD vs non-ILD: P = 0.0003, RP-ILD vs HC: P < 0.0001). Further analysis revealed that the kynurenine (KYN) pathway may primarily drive abnormal TRP metabolism in MDA5+ DM patients with RP-ILD. In addition, abnormal TRP and KYN pathway metabolites were associated with disease activity indicators in MDA5+ DM patients.

Conclusion: Our results indicated that alterations in the TRP metabolism may play an active role in the pathogenesis of RP-ILD in MDA5+ DM and could be considered as a potential therapeutic approach.

FIG 1. Non-targeted metabolomics profiling analysis of MDA5 positive dermatomyositis (MDA5+ DM) patients with rapidly progressive ILD (RP-ILD, n = 5), chronic ILD (C-ILD, n = 5), non-ILD (n = 5) and healthy controls (HCs, n = 5). (A) Score scatter plot of principal component analysis (PCA) model. (B) Score scatter plot of partial least squares discriminant analysis (PLS-DA) model. (C) Upset plot illustrating overlapping and specific metabolites in various comparison groups.

FIG 2. Enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for metabolites. (A) KEGG metabolic pathway classification statistics chart. Y-axis, the secondary classification of the KEGG metabolic pathway. X-axis, the number of compounds annotated under the pathway. (B) Difference abundance score chart of KEGG enrichment between RP-ILD and C-ILD. (C) Difference abundance score chart of KEGG enrichment between RP-ILD and non-ILD. (D) Difference abundance score chart of KEGG enrichment between RP-ILD and HC.

FIG 3. Amino acid pathway-specific metabolite abundance analysis. (A) Box plots showing distribution of metabolite abundance in tryptophan metabolism. (B) Box plots showing distribution of metabolite abundance in lysine metabolism. (C) Box plots showing distribution of metabolite abundance in arginine and proline metabolism. (* P < 0.05, ** P < 0.01, *** P < 0.001).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tryptophan-metabolism-alteration-is-associated-with-rapidly-progressive-interstitial-lung-disease-of-anti-mda5-dermatomyositis/