Risk factors and disease mechanisms in myositis

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.

Figure 1.. Possible pathways to idiopathic inflammatory myopathy phenotypes

The idiopathic inflammatory myopathies (IIM) probably consist of multiple phenotypes, each of which might be defined by unique combinations of symptoms, signs, and laboratory abnormalities. The major IIM phenotypes—polymyositis (PM), dermatomyositis (DM), necrotizing myopathy (NM), and inclusion body myositis (IBM)—are shown in the black circle at the bottom. Each phenotype could result from different pathogenic mechanisms, as represented by green circles (showing immunologic processes) and yellow circles (showing non-immunologic processes) in the center of the figure, because of the interactions between genetic risk factors (orange circles) and environmental risk factors (red circles). Some combinations of genotypes and environmental exposures induce certain mechanisms and disease phenotypes, whereas other combinations might have no effect or could be protective. C4A, complement 4A; DCs, dendritic cells, ER, endoplasmic reticulum; HLA, human leukocyte antigen; ROS, reactive oxygen species; UVR, ultraviolet radiation.

Figure 2.. Epidemiologic investigations of environmental agents and IIMs

Infectious and non-infectious agents associated with IIM phenotypes from epidemiologic studies suggest a wide array of risk factors with different strengths of association. 95% CI, 95% confidence interval; CTD, connective tissue disease; DM, dermatomyositis; GI, gastrointestinal; HLA, human leukocyte antigen; IIM, idiopathic inflammatory myopathies; JDM, juvenile dermatomyositis; JPM, juvenile polymyositis; OR, odds ratio; PM, polymyositis; RR, relative risk; URI, upper respiratory infection.

Figure 3.

Infectious and non-infectious agents evaluated in epidemiological studies suggest a wide array of risk and protective factors with different strengths of association with idiopathic inflammatory myopathy (IIM) phenotypes. CTD, connective tissue disease; OR, odds ratio; RR, relative risk. a. Infection in the year before IIM diagnosis. b. Infection in the year before IIM onset. c. Inflammatory lung disease at study inclusion.