Insights into pathogenesis and clinical implications in myositis-associated interstitial lung diseases

Curr Opin Pulm Med. 2020 Sep;26(5):507-517. doi: 10.1097/MCP.0000000000000698.

Abstract

Purpose of review: Interstitial lung diseases (ILDs) have been reported to be associated with myositis (including polymyositis and dermatomyositis). These myositis-associated ILDs carry significant morbidity and mortality. This review summarizes recent findings on myositis-associated ILD with a focus on pathogenesis and emerging treatment.

Recent findings: Recent advances in genetics have revealed 22 myositis-associated genome-wide loci, which were significantly enriched in regulatory regions in immune cells. An analysis of such disease-associated loci elucidated potential drug targets (e.g., TYK2 targeted by tofacitinib). In another study, an intronic variant in WDFY4 in association with clinically amyopathic dermatomyositis (CADM) had an effect for higher expression of a truncated WDFY4 isoform. Truncated WDFY4 markedly enhanced the MDA5-mediated NF-κB activation and cell apoptosis, indicating the dysregulated WDFY4-MDA5 pathway as a novel pathogenesis of CADM. As a novel strategy, tofacitinib treatment showed a promising improvement in survival and clinical features of CADM-associated ILD.

Summary: The genetic differences in the myositis-susceptible loci may explain the heterogeneous phenotypes and treatment responses in myositis-associated ILD. The understanding of pathogenesis with the genetic background as well as autoantibodies will enable the practice of personalized treatment in the management of the disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Apoptosis / genetics
  • Apoptosis / immunology
  • Autoantibodies / immunology*
  • Dermatomyositis / drug therapy
  • Dermatomyositis / genetics
  • Dermatomyositis / immunology
  • Humans
  • Interferon-Induced Helicase, IFIH1 / immunology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / immunology
  • Lung Diseases, Interstitial / drug therapy
  • Lung Diseases, Interstitial / genetics
  • Lung Diseases, Interstitial / immunology*
  • Molecular Targeted Therapy
  • Myositis / drug therapy
  • Myositis / genetics
  • Myositis / immunology*
  • NF-kappa B / immunology
  • Phenotype
  • Piperidines / therapeutic use
  • Polymyositis
  • Pyrimidines / therapeutic use
  • Signal Transduction
  • TYK2 Kinase / genetics
  • TYK2 Kinase / immunology

Substances

  • Autoantibodies
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Piperidines
  • Pyrimidines
  • WDFY4 protein, human
  • tofacitinib
  • TYK2 Kinase
  • TYK2 protein, human
  • IFIH1 protein, human
  • Interferon-Induced Helicase, IFIH1

Supplementary concepts

  • Amyopathic dermatomyositis