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Risk factors and disease mechanisms in myositis

Nature Reviews Rheumatology volume 14, pages 255–268 (2018)Cite this article

Subjects

Key Points

  • Multiple independent associations within the HLA 8.1 ancestral haplotype are the strongest genetic risk factors for idiopathic inflammatory myopathies (IIMs).

  • Although some associations overlap with those for other autoimmune diseases, other genetic risk factors are unique to certain IIM phenotypes, suggesting that these phenotypes have different pathophysiologies.

  • In addition to drug-induced myositis, epidemiological data support a role for infections, prior lung disease, physical exertion, collagen implants, ultraviolet radiation and smoking in the development of IIM phenotypes.

  • Although the disease mechanisms for IIM are ill-defined, both the innate immune system (including cytokines and chemokines) and adaptive immune system (including autoantibodies and antigen-specific T cells) are probably involved.

  • Several non-immune-mediated mechanisms contribute to IIM pathogenesis, including cell-stress pathways, free radicals, altered energy metabolism, protein homeostasis and mitochondrial damage.

  • Multidisciplinary collaborative approaches, focused use of resources and better investigative tools are needed to define additional risk and protective factors and pathogenic mechanisms, to cure and prevent the development of IIM.

Abstract

Autoimmune diseases develop as a result of chronic inflammation owing to interactions between genes and the environment. However, the mechanisms by which autoimmune diseases evolve remain poorly understood. Newly discovered risk factors and pathogenic processes in the various idiopathic inflammatory myopathy (IIM) phenotypes (known collectively as myositis) have illuminated innovative approaches for understanding these diseases. The HLA 8.1 ancestral haplotype is a key risk factor for major IIM phenotypes in some populations, and several genetic variants associated with other autoimmune diseases have been identified as IIM risk factors. Environmental risk factors are less well studied than genetic factors but might include viruses, bacteria, ultraviolet radiation, smoking, occupational and perinatal exposures and a growing list of drugs (including biologic agents) and dietary supplements. Disease mechanisms vary by phenotype, with evidence of shared innate and adaptive immune and metabolic pathways in some phenotypes but unique pathways in others. The heterogeneity and rarity of the IIMs make advancements in diagnosis and treatment cumbersome. Novel approaches, better-defined phenotypes, and international, multidisciplinary consensus have contributed to progress, and it is hoped that these methods will eventually enable therapeutic intervention before the onset or major progression of disease. In the future, preemptive strategies for IIM management might be possible.

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Figure 1: Possible pathways to idiopathic inflammatory myopathy phenotypes.
Figure 2: Epidemiological investigations of environmental agents and idiopathic inflammatory myopathies.
Figure 3: Immune-mediated and non-immune-mediated disease mechanisms in idiopathic inflammatory myopathies.

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Acknowledgements

The authors thank L. Rider, I. Lundberg, A. Mammen and C. Parks for many useful discussions of concepts in this area and for helpful comments on the manuscript, and are grateful to L. Maroski for her technical assistance. The authors' work is supported in part by the Intramural Research Program of the NIH National Institute of Environmental Health Sciences. K.N. is supported by the NIH (1R21AI128248-01, K26OD011171), The Myositis Association and the US Department of Defense (W81XWH-11-1-0809 (K.N. and F.W.M.), W81XWH-11-1-0782 (K.N.). J.L. is supported by the Medical Research Council, UK (MR/N003322/1) and The Myositis Association.

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Authors and Affiliations

  1. Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

    Frederick W. Miller

  2. Centre for Epidemiology, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, UK

    Janine A. Lamb

  3. Department of Neurology, University Medical Center Göttingen, Göttingen, Germany

    Jens Schmidt

  4. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY, USA

    Kanneboyina Nagaraju

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All authors researched data for the article, made substantial contributions to discussions of the content, wrote the article and contributed equally to reviewing and/or editing the manuscript before submission.

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Rimmed vacuoles

Spaces within the cytoplasm of a muscle cell with a purplish staining rim on trichrome staining.

Functional annotation

Characterization of the function assigned to each gene product or genetic variant.

Expression quantitative trait loci

(eQTLs). Genomic loci that regulate gene expression.

Macroautophagy

A process in which cellular contents are degraded by lysosomes or vacuoles and recycled.

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Miller, F., Lamb, J., Schmidt, J. et al. Risk factors and disease mechanisms in myositis. Nat Rev Rheumatol 14, 255–268 (2018). https://doi.org/10.1038/nrrheum.2018.48

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