Tryptophan metabolism alteration is associated with rapidly progressive interstitial lung disease of anti-MDA5+ dermatomyositis.

BACKGROUND

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, chronic ILD, 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) (RP-ILD vs C-ILD: P = 0.0006; RP-ILD vs non-ILD: P = 0.0003; RP-ILD vs HC: P < 0.0001), and its metabolites (5-Hydroxy-L-TRP, 5-Hydroxyindoleacetylglycine, Formyl-5-hydroxykynurenamine, L-Phenylalanine, 3-Hydroxyanthranilic acid and kynurenine (KYN)). Further analysis revealed that the 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 a potential role in the pathogenesis of RP-ILD in MDA5+ DM and could be considered as a promising therapeutic approach.