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Environmental Risks for Inflammatory Myopathies

  • Weng Ian Che
    Affiliations
    Department of Medicine, Solna, Eugeniahemmet, T2, Karolinska Universitetssjukhuset, Solna, Stockholm 171 76, Sweden

    Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
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  • Ingrid E. Lundberg
    Correspondence
    Corresponding author. Rheumatology, Karolinska University Hospital, Anna Steckséns gata 30A, Stockholm 171 76, Sweden.
    Affiliations
    Rheumatology, Karolinska University Hospital, Anna Steckséns gata 30A, Stockholm 171 76, Sweden

    Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden

    ME Gastro, Derm and Rheuma, Theme Inflammation and Aging, Karolinska University Hospital, Stockholm, Sweden
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  • Marie Holmqvist
    Affiliations
    Department of Medicine, Solna, Eugeniahemmet, T2, Karolinska Universitetssjukhuset, Solna, Stockholm 171 76, Sweden

    Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden

    Rheumatology, Karolinska University Hospital, Anna Steckséns gata 30A, Stockholm 171 76, Sweden

    Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
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      Keywords

      Key points

      • It has been suggested that the onset of idiopathic inflammatory myopathies (IIMs) requires environmental triggers besides underlying genetic susceptibility. Ultraviolet radiation, smoking, infectious agents, certain pollutants, medications, and vitamin D deficiency are potential environmental triggers for IIM.
      • Many of the suggested environmental factors for IIM enter human body via lungs and are related to features of lung involvement in IIM, supporting lung as the initial onset site of autoimmunity for some subgroups of IIM.
      • Some presented environmental factors are linked to specific IIM phenotypes and the presence of specific autoantibodies, such as anti-Mi2, anti-Jo1, and anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase autoantibodies, indicating the relevance of different environmental factors in different autoantibody-defined subgroups of IIM.
      • Future investigations should consider exploring the associations between environmental factors and subsets of IIM defined by autoantibody profile.

      Introduction

      Inflammatory myopathies are a group of heterogenous diseases. Some rare conditions in this group are associated with infections but the larger group, idiopathic inflammatory myopathies (IIMs), the focus of this review, does not have a causative agent. IIM is characterized by proximal muscle weakness accompanied by various extramuscular manifestations, for example, in skin, lungs, joints, heart, and gastrointestinal tract.
      • Lundberg I.E.
      • Fujimoto M.
      • Vencovsky J.
      • et al.
      Idiopathic inflammatory myopathies.
      ,
      • Aggarwal R.
      • Oddis C.V.
      Managing myositis: a practical guide.
      The major subtypes of IIM classified based on clinical, serologic, and histologic features are dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), antisynthetase syndrome (ASSD), immune-mediated necrotizing myopathy (IMNM), and juvenile IIM.
      • Lundberg I.E.
      • Fujimoto M.
      • Vencovsky J.
      • et al.
      Idiopathic inflammatory myopathies.
      More homogenous subsets can be identified by using myositis-specific and myositis-associated autoantibodies (MSAs and MAAs).
      • Lundberg I.E.
      • Fujimoto M.
      • Vencovsky J.
      • et al.
      Idiopathic inflammatory myopathies.
      The pathogenic mechanisms of IIM are complex and not fully understood but it has been suggested that the onset of IIM requires environmental triggers in genetically susceptible individuals.
      • O'Hanlon T.P.
      • Rider L.G.
      • Gan L.
      • et al.
      Gene expression profiles from discordant monozygotic twins suggest that molecular pathways are shared among multiple systemic autoimmune diseases.
      The geospatial and seasonal pattern of IIM onset as well as exposure to different environmental factors before the diagnosis of IIM have been studied and findings suggest associations between various environmental factors and IIM
      • Aguilar-Vazquez A.
      • Chavarria-Avila E.
      • Pizano-Martinez O.
      • et al.
      Geographical Latitude Remains as an Important Factor for the Prevalence of Some Myositis Autoantibodies: A Systematic Review.
      • Mamyrova G.
      • Rider L.G.
      • Ehrlich A.
      • et al.
      Environmental factors associated with disease flare in juvenile and adult dermatomyositis.
      • Griger Z.
      • Csige I.
      • Vincze M.
      • et al.
      Smoking and alcohol consumption may increase the development of anti-jo-1 antibodies in patients with idiopathic inflammatory myopathies.
      • Lyon M.G.
      • Bloch D.A.
      • Hollak B.
      • et al.
      Predisposing factors in polymyositis-dermatomyositis: results of a nationwide survey.
      • Sarkar K.
      • Weinberg C.R.
      • Oddis C.V.
      • et al.
      Seasonal influence on the onset of idiopathic inflammatory myopathies in serologically defined groups.
      but only a few of them have been reproduced in large-scale studies with comparison to the general population.
      • Blanc P.D.
      • Järvholm B.
      • Torén K.
      Prospective risk of rheumatologic disease associated with occupational exposure in a cohort of male construction workers.
      • Ying D.V.
      • Schmajuk G.
      • Trupin L.
      • et al.
      Inorganic Dust Exposure During Military Service as a Predictor of Rheumatoid Arthritis and Other Autoimmune Conditions.
      • Nielsen P.R.
      • Kragstrup T.W.
      • Deleuran B.W.
      • et al.
      Infections as risk factor for autoimmune diseases - A nationwide study.
      • Svensson J.
      • Holmqvist M.
      • Lundberg I.E.
      • et al.
      Infections and respiratory tract disease as risk factors for idiopathic inflammatory myopathies: a population-based case-control study.
      In this review, we systemically review and discuss the external environmental factors with suggestive evidence mainly from cross-sectional, case-control, and cohort studies for adult-onset IIM (Table 1). We also highlight their potential implications in IIM development, identify current challenges, and provide insight into future investigation.
      Table 1Environmental factors and their associations with idiopathic inflammatory myopathies and related features
      FactorsAssociationIIM PhenotypesMSAsGenetic FactorsEvidence from
      UV radiationRiskDMAnti-Mi2
      • Aguilar-Vazquez A.
      • Chavarria-Avila E.
      • Pizano-Martinez O.
      • et al.
      Geographical Latitude Remains as an Important Factor for the Prevalence of Some Myositis Autoantibodies: A Systematic Review.
      ,
      • Okada S.
      • Weatherhead E.
      • Targoff I.N.
      • et al.
      Int Myositis Collab Study G. Global surface ultraviolet radiation intensity may modulate the clinical and immunologic expression of autoimmune muscle disease.
      • Love L.A.
      • Weinberg C.R.
      • McConnaughey D.R.
      • et al.
      Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women.
      • Parks C.G.
      • Wilkerson J.
      • Rose K.M.
      • et al.
      Association of Ultraviolet Radiation Exposure With Dermatomyositis in a National Myositis Patient Registry.
      SmokingRiskPMAnti-Jo1HLA-DRB1∗03:01
      • Chinoy H.
      • Adimulam S.
      • Marriage F.
      • et al.
      Interaction of HLA-DRB1∗03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study.
      • Pipis N.
      • Rothwell S.
      • Cooper R.
      • et al.
      Gene-Environmental Interaction of HLA-DRB1∗03:01 and Smoking for the Development of Anti-Jo-1 Autoantibodies in Idiopathic Inflammatory Myopathies: A UK Study.
      • Schiffenbauer A.
      • Faghihi-Kashani S.
      • O'Hanlon T.P.
      • et al.
      The effect of cigarette smoking on the clinical and serological phenotypes of polymyositis and dermatomyositis.
      ProtectiveAnti-TIF1γHLA-DRB1∗03:01
      Pollutants
       SilicaRiskDM
      Evidence from combined analyses including other autoimmune diseases.
      Anti-Jo1
      Based on descriptive data.
      • Blanc P.D.
      • Järvholm B.
      • Torén K.
      Prospective risk of rheumatologic disease associated with occupational exposure in a cohort of male construction workers.
      ,
      • Koeger A.C.
      • Lang T.
      • Alcaix D.
      • et al.
      Silica-associated connective tissue disease. A study of 24 cases.
       Inorganic dustRiskIIM
      Evidence from combined analyses including other autoimmune diseases.
      • Ying D.V.
      • Schmajuk G.
      • Trupin L.
      • et al.
      Inorganic Dust Exposure During Military Service as a Predictor of Rheumatoid Arthritis and Other Autoimmune Conditions.
       Dust, gas, fumeRiskASSD
      • Labirua-Iturburu A.
      • Selva-O'Callaghan A.
      • Zock J.P.
      • et al.
      Occupational exposure in patients with the antisynthetase syndrome.
       World Trade Center dustRiskDM/PM
      Evidence from combined analyses including other autoimmune diseases.
      Anti-Jo1
      Based on descriptive data.
      • Webber M.P.
      • Moir W.
      • Zeig-Owens R.
      • et al.
      Nested Case-Control Study of Selected Systemic Autoimmune Diseases in World Trade Center Rescue/Recovery Workers.
      ,
      • Selva-O'Callaghan A.
      • Labirua-Iturburu A.
      • Pinal-Fernandez I.
      Antisynthetase antibodies in World Trade Center rescue and recovery workers with inflammatory myositis: comment on the article by Webber et al.
       Infectious agentsRiskDM

      ASSD

      IMNM

      IBM

      PM
      Anti-TIF1γ
      Based on serologic data.


      Anti-MDA5
      Based on descriptive data.
      • Nielsen P.R.
      • Kragstrup T.W.
      • Deleuran B.W.
      • et al.
      Infections as risk factor for autoimmune diseases - A nationwide study.
      ,
      • Svensson J.
      • Holmqvist M.
      • Lundberg I.E.
      • et al.
      Infections and respiratory tract disease as risk factors for idiopathic inflammatory myopathies: a population-based case-control study.
      ,
      • Rider L.G.
      • Farhadi P.N.
      • Bayat N.
      • et al.
      Infections and medications associated with onset of myositis in myovision, a national myositis patient registry.
      • Kalinova D.
      • Todorova E.
      • Kyurkchiev D.
      • et al.
      AB0493 Association between antiviral IGM antibodies and myositis autoantibodies in patients with autoimmune myositis in Bulgarian population.
      • Barzilai O.
      • Sherer Y.
      • Ram M.
      • et al.
      Epstein-Barr virus and cytomegalovirus in autoimmune diseases - Are they truly notorious? A preliminary report.
      • Uruha A.
      • Noguchi S.
      • Hayashi Y.K.
      • et al.
      Hepatitis C virus infection in inclusion body myositis: A case-control study.
      • Megremis S.
      • Walker T.D.J.
      • He X.
      • et al.
      Analysis of human total antibody repertoires in TIF1gamma autoantibody positive dermatomyositis.
      ,
      • Gokhale Y.
      • Patankar A.
      • Holla U.
      • et al.
      Dermatomyositis during COVID-19 Pandemic (A Case Series): Is there a Cause Effect Relationship?.
      • Balseiro A.
      • Oleaga A.
      • Polledo L.
      • et al.
      Clostridium sordellii in a Brown Bear (Ursus arctos) from Spain.
      • Helmers S.B.
      • Jiang X.
      • Pettersson D.
      • et al.
      Inflammatory lung disease a potential risk factor for onset of idiopathic inflammatory myopathies: results from a pilot study.
      Medications
       StatinsRiskIMNM

      DM

      PM
      Anti-HMGCRHLA-DRB1∗11:01
      • Rider L.G.
      • Farhadi P.N.
      • Bayat N.
      • et al.
      Infections and medications associated with onset of myositis in myovision, a national myositis patient registry.
      ,
      • Christopher-Stine L.
      • Casciola-Rosen L.A.
      • Hong G.
      • et al.
      A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy.
      ,
      • Wu Y.F.
      • Lach B.
      • Provias J.P.
      • et al.
      Statin-associated Autoimmune Myopathies: A Pathophysiologic Spectrum.
      ,
      • Sailler L.
      • Pereira C.
      • Bagheri A.
      • et al.
      Increased exposure to statins in patients developing chronic muscle diseases: a 2-year retrospective study.
      ,
      • Caughey G.E.
      • Gabb G.M.
      • Ronson S.
      • et al.
      Association of Statin Exposure With Histologically Confirmed Idiopathic Inflammatory Myositis in an Australian Population.
      ,
      • Tiniakou E.
      • Pinal-Fernandez I.
      • Lloyd T.E.
      • et al.
      More severe disease and slower recovery in younger patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy.
      ,
      • Ge Y.
      • Lu X.
      • Peng Q.
      • et al.
      Clinical Characteristics of Anti-3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Antibodies in Chinese Patients with Idiopathic Inflammatory Myopathies.
       Immune checkpoint inhibitorsRiskIIM
      • Lee J.-W.
      • Lee S.-M.
      • Gwak K.-S.
      • et al.
      Screening of edible mushrooms for the production of lovastatin and its HMG-CoA reductase inhibitory activity.
      • Yoshida T.
      • Chikazawa H.
      • Kumon Y.
      • et al.
      Did Shiitake Mushrooms Induce Immune-Mediated Necrotizing Myopathy?.
      • Barbacki A.
      • Fallavollita S.A.
      • Karamchandani J.
      • et al.
      Immune-Mediated Necrotizing Myopathy and Dietary Sources of Statins.
      • Mammen A.L.
      • Chung T.
      • Christopher-Stine L.
      • et al.
      Autoantibodies Against 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase in Patients With Statin-Associated Autoimmune Myopathy.
      Vitamin D deficiencyRiskIIMAnti-Jo1

      Anti-Mi2
      • Close R.M.
      • Close L.M.
      • Galdun P.
      • et al.
      Potential implications of six American Indian patients with myopathy, statin exposure and anti-HMGCR antibodies.
      ,
      • Aldrich J.
      • Pundole X.
      • Tummala S.
      • et al.
      Inflammatory Myositis in Cancer Patients Receiving Immune Checkpoint Inhibitors.
      Abbreviations: ASSD, antisynthetase syndrome; DM, dermatomyositis; HLA-DRB1, major histocompatibility complex, class II, DR beta 1; IBM, inclusion body myositis; IIM, idiopathic inflammatory myopathies; ILD, interstitial lung disease; IMNM, immune-mediated necrotizing myopathy; MDA5, melanoma differentiation-associated gene 5; MSAs, myositis-specific autoantibodies; PM, polymyositis; TIF1γ, transcriptional intermediary factor 1γ; UV, ultraviolet.
      a Based on descriptive data.
      b Evidence from combined analyses including other autoimmune diseases.
      c Based on serologic data.

      Ultraviolet Radiation

      Ultraviolet (UV) radiation has long been considered a risk factor for IIM, in particular for DM. The supportive evidence include (1) photosensitivity being a common cutaneous manifestation associated with DM
      • Aggarwal R.
      • Oddis C.V.
      Managing myositis: a practical guide.
      , (2) prevalence of DM showing a geographic gradient negatively correlated with latitude
      • Dourmishev L.
      • Meffert H.
      • Piazena H.
      Dermatomyositis: comparative studies of cutaneous photosensitivity in lupus erythematosus and normal subjects.
      ,
      • Hengstman G.J.
      • van Venrooij W.J.
      • Vencovsky J.
      • et al.
      The relative prevalence of dermatomyositis and polymyositis in Europe exhibits a latitudinal gradient.
      , and (3) prevalence of DM positively associated with UV radiation intensity.
      • Okada S.
      • Weatherhead E.
      • Targoff I.N.
      • et al.
      Int Myositis Collab Study G. Global surface ultraviolet radiation intensity may modulate the clinical and immunologic expression of autoimmune muscle disease.
      ,
      • Love L.A.
      • Weinberg C.R.
      • McConnaughey D.R.
      • et al.
      Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women.
      The association between UV radiation and the development of DM is further supported by evidence from the study using MYOVISION registry data. Based on the self-reported data on sun exposure in 1,350 patients, patients with DM were more likely to experience 2 times or more of sunburn and high/moderate job-related sun exposure 12 months before disease diagnosis than patients with PM or IBM.
      • Parks C.G.
      • Wilkerson J.
      • Rose K.M.
      • et al.
      Association of Ultraviolet Radiation Exposure With Dermatomyositis in a National Myositis Patient Registry.
      Moreover, sun exposure may not only confer the risk of DM development but also DM flare.
      • Mamyrova G.
      • Rider L.G.
      • Ehrlich A.
      • et al.
      Environmental factors associated with disease flare in juvenile and adult dermatomyositis.
      The association between UV radiation and presence of some MSAs/MAAs has been examined, and a positive correlation between the prevalence of DM-specific anti-Mi2 autoantibodies and UV radiation has been suggested.
      • Okada S.
      • Weatherhead E.
      • Targoff I.N.
      • et al.
      Int Myositis Collab Study G. Global surface ultraviolet radiation intensity may modulate the clinical and immunologic expression of autoimmune muscle disease.
      ,
      • Love L.A.
      • Weinberg C.R.
      • McConnaughey D.R.
      • et al.
      Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women.
      A systematic review analyzing prevalence data from 92 studies across 22 countries showed a significant trend of increasing prevalence of anti-Mi2 autoantibodies with lower latitudes, whereas the trend to increase in higher global solar UV index (UVI) was not significant.
      • Aguilar-Vazquez A.
      • Chavarria-Avila E.
      • Pizano-Martinez O.
      • et al.
      Geographical Latitude Remains as an Important Factor for the Prevalence of Some Myositis Autoantibodies: A Systematic Review.
      Because UVI was estimated based on data in 2010 while data collection of the included studies spread over a much wider time period (up to 10 years), and because UV radiation was correlated with latitude, it was suggested that analyses of geographic gradient might provide more precise findings than UVI.
      • Aguilar-Vazquez A.
      • Chavarria-Avila E.
      • Pizano-Martinez O.
      • et al.
      Geographical Latitude Remains as an Important Factor for the Prevalence of Some Myositis Autoantibodies: A Systematic Review.
      Interestingly, the review study also first reported positive associations with UVI for anti-Ro52, anti-PM-Scl, and anti-Ku autoantibodies and a negative association for anti-threonyl-tRNA synthetase autoantibodies,
      • Aguilar-Vazquez A.
      • Chavarria-Avila E.
      • Pizano-Martinez O.
      • et al.
      Geographical Latitude Remains as an Important Factor for the Prevalence of Some Myositis Autoantibodies: A Systematic Review.
      suggesting that UV radiation may affect the development of other IIM phenotypes besides DM. Further investigation of these associations is warranted given the limitations, such as cross-sectional design and lack of measurement of personal exposure to UV radiation, of the included studies.
      • Aguilar-Vazquez A.
      • Chavarria-Avila E.
      • Pizano-Martinez O.
      • et al.
      Geographical Latitude Remains as an Important Factor for the Prevalence of Some Myositis Autoantibodies: A Systematic Review.
      ,
      • Okada S.
      • Weatherhead E.
      • Targoff I.N.
      • et al.
      Int Myositis Collab Study G. Global surface ultraviolet radiation intensity may modulate the clinical and immunologic expression of autoimmune muscle disease.
      ,
      • Love L.A.
      • Weinberg C.R.
      • McConnaughey D.R.
      • et al.
      Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women.
      It has also been suggested that associations between UV radiation and DM and anti-Mi2 autoantibodies differ across sex and ethnicity. The risk of having DM and anti-Mi2 autoantibodies associated with UV radiation and sunburn was solely significant in women, whereas the association between occupational sun exposure and DM was more apparent in men.
      • Love L.A.
      • Weinberg C.R.
      • McConnaughey D.R.
      • et al.
      Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women.
      ,
      • Parks C.G.
      • Wilkerson J.
      • Rose K.M.
      • et al.
      Association of Ultraviolet Radiation Exposure With Dermatomyositis in a National Myositis Patient Registry.
      Moreover, UV radiation was more likely a risk factor of DM and anti-Mi2 autoantibodies in Caucasian populations than in non-Caucasian populations.
      • Love L.A.
      • Weinberg C.R.
      • McConnaughey D.R.
      • et al.
      Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women.
      The absence of associations in men and in non-Caucasian populations could be due to small sample size because most patients included were women and Caucasians.
      • Love L.A.
      • Weinberg C.R.
      • McConnaughey D.R.
      • et al.
      Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women.
      ,
      • Parks C.G.
      • Wilkerson J.
      • Rose K.M.
      • et al.
      Association of Ultraviolet Radiation Exposure With Dermatomyositis in a National Myositis Patient Registry.
      It is not fully known how UV radiation may trigger the onset of DM but there are findings showing upregulation of the Mi2 protein but not the other subunits of the nucleosome remodeling and deacetylase complex in keratinocytes shortly after 30 minutes exposure to UV treatment.
      • Burd C.J.
      • Kinyamu H.K.
      • Miller F.W.
      • et al.
      UV Radiation Regulates Mi-2 through Protein Translation and Stability.
      In addition, upregulations of Mi2 protein after UV exposure were also noted in several cancer cell types. In addition, ionizing radiation that cause DNA damage could also result in rapid accumulation of Mi2 protein.
      • Burd C.J.
      • Kinyamu H.K.
      • Miller F.W.
      • et al.
      UV Radiation Regulates Mi-2 through Protein Translation and Stability.
      These findings combined suggest that UV radiation may contribute to the development of DM by causing DNA damage and by increasing antigen presentation in the affected cells.
      • Burd C.J.
      • Kinyamu H.K.
      • Miller F.W.
      • et al.
      UV Radiation Regulates Mi-2 through Protein Translation and Stability.

      Smoking

      Smoking has been found to confer an increased risk for anti-Jo1 autoantibodies in particular in genetically susceptible individuals with IIM. Anti-Jo1 positive patients were more likely to have a smoking history than anti-Jo1 negative patients.
      • Griger Z.
      • Csige I.
      • Vincze M.
      • et al.
      Smoking and alcohol consumption may increase the development of anti-jo-1 antibodies in patients with idiopathic inflammatory myopathies.
      ,
      • Chinoy H.
      • Adimulam S.
      • Marriage F.
      • et al.
      Interaction of HLA-DRB1∗03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study.
      Smokers with IIM carrying allele in the major histocompatibility complex, class II, DR beta 1 gene (HLA-DRB1∗03) had the greatest risk of anti-Jo1 autoantibody positivity compared with other combinations of smoking history and positivity of anti-Jo1 autoantibodies among patients with IIM.
      • Chinoy H.
      • Adimulam S.
      • Marriage F.
      • et al.
      Interaction of HLA-DRB1∗03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study.
      Consistent findings were noted in the analysis stratified by sex but women had a stronger association than men.
      • Chinoy H.
      • Adimulam S.
      • Marriage F.
      • et al.
      Interaction of HLA-DRB1∗03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study.
      A follow-up study with higher resolution imputation data found an even stronger association between anti-Jo1 autoantibodies and smoking in HLA-DRB1∗03:01 positive patients.
      • Pipis N.
      • Rothwell S.
      • Cooper R.
      • et al.
      Gene-Environmental Interaction of HLA-DRB1∗03:01 and Smoking for the Development of Anti-Jo-1 Autoantibodies in Idiopathic Inflammatory Myopathies: A UK Study.
      Interactions on the multiplicative scale between HLA-DRB1∗03/∗03:01 allele and smoking when modeling the risk of anti-Jo1 autoantibodies has been tested without significant interaction, potentially due to lack of power.
      • Chinoy H.
      • Adimulam S.
      • Marriage F.
      • et al.
      Interaction of HLA-DRB1∗03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study.
      ,
      • Pipis N.
      • Rothwell S.
      • Cooper R.
      • et al.
      Gene-Environmental Interaction of HLA-DRB1∗03:01 and Smoking for the Development of Anti-Jo-1 Autoantibodies in Idiopathic Inflammatory Myopathies: A UK Study.
      It has also been suggested that the association between smoking and anti-Jo1 autoantibodies could be independent of HLA-DRB1∗03:01.
      • Pipis N.
      • Rothwell S.
      • Cooper R.
      • et al.
      Gene-Environmental Interaction of HLA-DRB1∗03:01 and Smoking for the Development of Anti-Jo-1 Autoantibodies in Idiopathic Inflammatory Myopathies: A UK Study.
      Together, these findings indicate that smoking is a risk factor of developing the anti-Jo1 autoantibodies and confers an additional risk in patients carrying HLA-DRB1∗03:01 allele.
      There is a study analyzing smoking in pack-years and reporting that the likelihood was increased by 2% for PM and IIM-associated interstitial lung disease (ILD) and by 1% for anti-Jo1 autoantibodies but was decreased by 7% for anti-transcriptional intermediary factor 1 α/γ (TIF1α/γ) autoantibodies for every increased unit of pack-years.
      • Schiffenbauer A.
      • Faghihi-Kashani S.
      • O'Hanlon T.P.
      • et al.
      The effect of cigarette smoking on the clinical and serological phenotypes of polymyositis and dermatomyositis.
      However, the estimate for anti-Jo1 autoantibodies was not statistically significant.
      • Schiffenbauer A.
      • Faghihi-Kashani S.
      • O'Hanlon T.P.
      • et al.
      The effect of cigarette smoking on the clinical and serological phenotypes of polymyositis and dermatomyositis.
      Similar associations were observed in the analyses including only Caucasian patients while no significant associations were noted in African American patients, probably due to a smaller number of patients.
      • Schiffenbauer A.
      • Faghihi-Kashani S.
      • O'Hanlon T.P.
      • et al.
      The effect of cigarette smoking on the clinical and serological phenotypes of polymyositis and dermatomyositis.
      Importantly, this study also revealed that smoking had the strongest positive associations with PM, ILD, and anti-Jo1 autoantibodies, as well as a greatest inverse association with anti-TIF1α/γ autoantibodies in patients with HLA-DRB1∗03:01 allele.
      • Schiffenbauer A.
      • Faghihi-Kashani S.
      • O'Hanlon T.P.
      • et al.
      The effect of cigarette smoking on the clinical and serological phenotypes of polymyositis and dermatomyositis.
      In summary, although lack of evidence from studies with longitudinal data raises uncertainty of a causal link between smoking and IIM, observational data support that smoking may have a role in the pathogenesis of anti-Jo1 positive IIM, potentially by triggering the development of anti-Jo1 autoantibodies in susceptible individuals carrying HLA-DRB1∗03:01 allele.

      Pollutants

      A wide range of environmental pollutants has been reported to potentially trigger the onset of IIM. Earlier case series found that some DM patients had long-term occupational exposure to silica or organic solvents before disease onset.
      • Goldman J.A.
      Connective tissue disease in people exposed to organic chemical solvents: systemic sclerosis (scleroderma) in dry cleaning plant and aircraft industry workers.
      ,
      • Koeger A.C.
      • Lang T.
      • Alcaix D.
      • et al.
      Silica-associated connective tissue disease. A study of 24 cases.
      The association between silica and DM has been examined further in a Swedish cohort study including 241,077 men employed in the construction industry.
      • Blanc P.D.
      • Järvholm B.
      • Torén K.
      Prospective risk of rheumatologic disease associated with occupational exposure in a cohort of male construction workers.
      This study revealed that the risk of developing systemic lupus erythematosus, systemic sclerosis (SSc), or DM was almost doubled in workers exposed to silica dust compared with those unexposed office workers after controlling for age and smoking.
      • Blanc P.D.
      • Järvholm B.
      • Torén K.
      Prospective risk of rheumatologic disease associated with occupational exposure in a cohort of male construction workers.
      A recent study including 438,068 US discharge military veterans found that the odds of SSc, vasculitis, or IIM was significantly increased by 23% for those exposed to inorganic dust during services in Afghanistan or in Iraq than those unexposed after adjusting for age, sex, race, and smoking status, and the association became stronger as the length of service was increased.
      • Ying D.V.
      • Schmajuk G.
      • Trupin L.
      • et al.
      Inorganic Dust Exposure During Military Service as a Predictor of Rheumatoid Arthritis and Other Autoimmune Conditions.
      There is more evidence supporting a role of occupational pollutants in the pathogenesis of ASSD compared with other IIM phenotypes although findings are based on self-reported case-control data, and might therefore be subject to recall bias,
      • Labirua-Iturburu A.
      • Selva-O'Callaghan A.
      • Zock J.P.
      • et al.
      Occupational exposure in patients with the antisynthetase syndrome.
      and some more descriptive data.
      • Koeger A.C.
      • Lang T.
      • Alcaix D.
      • et al.
      Silica-associated connective tissue disease. A study of 24 cases.
      ,
      • Campos G.
      • Eisenreich M.A.
      • Lopes L.M.
      • et al.
      Antisynthetase syndrome after acute massive inhalation of wood and paint dust.
      • Webber M.P.
      • Moir W.
      • Zeig-Owens R.
      • et al.
      Nested Case-Control Study of Selected Systemic Autoimmune Diseases in World Trade Center Rescue/Recovery Workers.
      • Selva-O'Callaghan A.
      • Labirua-Iturburu A.
      • Pinal-Fernandez I.
      Antisynthetase antibodies in World Trade Center rescue and recovery workers with inflammatory myositis: comment on the article by Webber et al.
      • Kawassaki A.M.
      • Kairalla R.A.
      • Carvalho C.R.
      • et al.
      Hypersensitive pneumonitis: A trigger of autoimmunity in inflammatory myositis - A case series.
      A case-control study observed a significantly higher frequency of lifetime occupational exposure to dust, gases, or fumes in 32 patients with ASSD (n = 25) or ILD (n = 7) than 32 IIM patients without ASSD (50% vs 22%).
      • Labirua-Iturburu A.
      • Selva-O'Callaghan A.
      • Zock J.P.
      • et al.
      Occupational exposure in patients with the antisynthetase syndrome.
      Moreover, patients with ASSD with high occupational exposure (94%) were more likely to have ILD than those exposed to no or low occupational pollutants (75%).
      • Labirua-Iturburu A.
      • Selva-O'Callaghan A.
      • Zock J.P.
      • et al.
      Occupational exposure in patients with the antisynthetase syndrome.
      Furthermore, a high likelihood of anti-Jo1 autoantibody positivity was observed in several studies investigating the association between environmental exposure and risk of autoimmune diseases. Both acute and chronic exposures to aerosolized World Trade Center dust after the 9/11 attack in firefighters were associated with increased risk of autoimmune diseases.
      • Webber M.P.
      • Moir W.
      • Zeig-Owens R.
      • et al.
      Nested Case-Control Study of Selected Systemic Autoimmune Diseases in World Trade Center Rescue/Recovery Workers.
      Among the identified autoimmune diseases, there were 8 cases of DM/PM and 2 of them were positive to anti-Jo1 autoantibodies.
      • Webber M.P.
      • Moir W.
      • Zeig-Owens R.
      • et al.
      Nested Case-Control Study of Selected Systemic Autoimmune Diseases in World Trade Center Rescue/Recovery Workers.
      ,
      • Selva-O'Callaghan A.
      • Labirua-Iturburu A.
      • Pinal-Fernandez I.
      Antisynthetase antibodies in World Trade Center rescue and recovery workers with inflammatory myositis: comment on the article by Webber et al.
      In a study of 10 patients with ASSD, 6 had hypersensitivity pneumonitis preceding the onset of ASSD, 9 were exposed to significant levels of domiciliary exposures including mold, birds, pigeon and feather pillow, and 6 were anti-Jo1 positive.
      • Kawassaki A.M.
      • Kairalla R.A.
      • Carvalho C.R.
      • et al.
      Hypersensitive pneumonitis: A trigger of autoimmunity in inflammatory myositis - A case series.
      One of the 3 patients with silica-associated DM was with the presence of anti-Jo1 autoantibodies.
      • Koeger A.C.
      • Lang T.
      • Alcaix D.
      • et al.
      Silica-associated connective tissue disease. A study of 24 cases.
      These findings suggest a triggering role of environmental pollutants in onset of autoimmunity, perhaps in lungs, which may result in systemic onset of autoimmunity later affecting other tissues.

      Infectious Agents

      Seasonality of birth or IIM disease onset observed in several studies suggests a nonrandom disease development, which may be affected by environmental exposures with a seasonal pattern such as infectious agents.
      • So H.
      • Shen Y.
      • Wong T.L.V.
      • et al.
      Seasonal variation in idiopathic inflammatory myopathies incidence and presentation: A retrospective study in Beijing and Hong Kong.
      • Nishina N.
      • Sato S.
      • Masui K.
      • et al.
      Seasonal and residential clustering at disease onset of anti-MDA5-associated interstitial lung disease.
      • Toquet S.
      • Granger B.
      • Uzunhan Y.
      • et al.
      The seasonality of Dermatomyositis associated with anti-MDA5 antibody: An argument for a respiratory viral trigger.
      • Woodman R.
      • Hakendorf P.
      • Limaye V.
      Seasonality of birth patterns in an Australian cohort of patients with biopsy-confirmed idiopathic inflammatory myopathy.
      For example, there are studies reporting aggregations of disease onset of patients with antimelanoma differentiation-associated gene 5 (MDA5) autoantibodies in winter where flu season coincided.
      • So H.
      • Shen Y.
      • Wong T.L.V.
      • et al.
      Seasonal variation in idiopathic inflammatory myopathies incidence and presentation: A retrospective study in Beijing and Hong Kong.
      ,
      • Nishina N.
      • Sato S.
      • Masui K.
      • et al.
      Seasonal and residential clustering at disease onset of anti-MDA5-associated interstitial lung disease.
      ,
      • Rath B.
      • Conrad T.
      • Myles P.
      • et al.
      Influenza and other respiratory viruses: standardizing disease severity in surveillance and clinical trials.
      However, no causal inference could be drawn from these seasonal patterns.
      The role of infectious agents in pathogenesis of IIM implicated by seasonality is further supported by the epidemiologic findings of preceding infections in patients with IIM. A nationwide cohort study in Denmark noted that the risk of DM/PM in individuals with history of hospital contact for viral, bacterial, and other infections was significantly increased and was 2-fold higher than those without hospital contact for infections after adjusting for calendar year, sex and its interaction with age, and comorbidities.
      • Nielsen P.R.
      • Kragstrup T.W.
      • Deleuran B.W.
      • et al.
      Infections as risk factor for autoimmune diseases - A nationwide study.
      Furthermore, this association was strengthened when the number of hospitalizations increased and as the time since hospitalization with an infection to diagnosis of DM/PM decreased.
      • Nielsen P.R.
      • Kragstrup T.W.
      • Deleuran B.W.
      • et al.
      Infections as risk factor for autoimmune diseases - A nationwide study.
      These findings are in line with the results of 2 case-control studies.
      • Svensson J.
      • Holmqvist M.
      • Lundberg I.E.
      • et al.
      Infections and respiratory tract disease as risk factors for idiopathic inflammatory myopathies: a population-based case-control study.
      ,
      • Rider L.G.
      • Farhadi P.N.
      • Bayat N.
      • et al.
      Infections and medications associated with onset of myositis in myovision, a national myositis patient registry.
      In one of the studies, the risk of reverse causality was minimized by excluding infections diagnosed in the year of IIM diagnosis.
      • Svensson J.
      • Holmqvist M.
      • Lundberg I.E.
      • et al.
      Infections and respiratory tract disease as risk factors for idiopathic inflammatory myopathies: a population-based case-control study.
      Specifically, the types of infections associated with IIM were mainly respiratory and gastrointestinal infections.
      • Svensson J.
      • Holmqvist M.
      • Lundberg I.E.
      • et al.
      Infections and respiratory tract disease as risk factors for idiopathic inflammatory myopathies: a population-based case-control study.
      ,
      • Rider L.G.
      • Farhadi P.N.
      • Bayat N.
      • et al.
      Infections and medications associated with onset of myositis in myovision, a national myositis patient registry.
      Serologic evidence suggests that the link between previous infection and IIM may be attributable to certain microbial agents, particularly viruses. Higher titers of antibodies against hepatitis C virus, Epstein-Barr virus (EBV), influenza A and B, parainfluenza, coxsackie virus, or cytomegalovirus (CMV) in patients with IIM than in controls were observed in several studies.
      • Kalinova D.
      • Todorova E.
      • Kyurkchiev D.
      • et al.
      AB0493 Association between antiviral IGM antibodies and myositis autoantibodies in patients with autoimmune myositis in Bulgarian population.
      • Barzilai O.
      • Sherer Y.
      • Ram M.
      • et al.
      Epstein-Barr virus and cytomegalovirus in autoimmune diseases - Are they truly notorious? A preliminary report.
      • Uruha A.
      • Noguchi S.
      • Hayashi Y.K.
      • et al.
      Hepatitis C virus infection in inclusion body myositis: A case-control study.
      A recent case-control study also found that antibodies against viral families of Coronaviridae, Geminiviridae, Herpesviridae, Orthomyxoviridae, and Poxviridae in adult patients with anti-TIF1γ autoantibodies were enriched, whereas the enriched viral families in matched healthy controls were Picornaviridae, Caliciviridae, Orthomyxoviridae, Coronaviridae, and Retroviridae.
      • Megremis S.
      • Walker T.D.J.
      • He X.
      • et al.
      Analysis of human total antibody repertoires in TIF1gamma autoantibody positive dermatomyositis.
      Specifically, a previous study found that, in comparison to matched healthy controls, patients with PM had higher levels of immunoglobulin M (IgM) and immunoglobulin G (IgG) against EBV, and IgM against CMV.
      • Barzilai O.
      • Sherer Y.
      • Ram M.
      • et al.
      Epstein-Barr virus and cytomegalovirus in autoimmune diseases - Are they truly notorious? A preliminary report.
      Interestingly, infiltrates of CD4+ CD28null T cells in muscle biopsies of patients with DM has been found solely in patients with IgG against CMV and not in patients without.
      • Fasth A.E.
      • Dastmalchi M.
      • Rahbar A.
      • et al.
      T cell infiltrates in the muscles of patients with dermatomyositis and polymyositis are dominated by CD28null T cells.
      Although no causality between these viral species and onset of IIM can be drawn from these serologic findings, they support the hypothesis for a role of acute (IgM) or latent (IgG) infection in the development of IIM.
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has also been suggested as a trigger of IIM. The evidence supporting this assumption is weak, and includes the presence of DM-specific autoantibodies including anti-MDA5 and antinuclear matrix protein 2 autoantibodies in patients with coronavirus diseases 19 (COVID-19),
      • De Santis M.
      • Isailovic N.
      • Motta F.
      • et al.
      Environmental triggers for connective tissue disease: the case of COVID-19 associated with dermatomyositis-specific autoantibodies.
      and a remarkable similarity of pathophysiological features between autoimmune anti-MDA5 syndrome and COVID-19
      • Giannini M.
      • Ohana M.
      • Nespola B.
      • et al.
      Similarities between COVID-19 and anti-MDA5 syndrome: what can we learn for better care?.
      and onset of the DM subgroup presenting with anti-MDA5 autoantibodies.
      • Gokhale Y.
      • Patankar A.
      • Holla U.
      • et al.
      Dermatomyositis during COVID-19 Pandemic (A Case Series): Is there a Cause Effect Relationship?.
      However, acute-onset IIM related to COVID-19 could be a transient epiphenomenon.
      • Gokhale Y.
      • Patankar A.
      • Holla U.
      • et al.
      Dermatomyositis during COVID-19 Pandemic (A Case Series): Is there a Cause Effect Relationship?.
      Future studies with longer follow-up time are warranted to evaluate if COVID-19 is associated with chronic IIM evolved from acute IIM.
      It is still unclear how microbes may trigger the onset of IIM but the abovementioned observations suggest a potential linkage to lung involvement in IIM.
      • Svensson J.
      • Holmqvist M.
      • Lundberg I.E.
      • et al.
      Infections and respiratory tract disease as risk factors for idiopathic inflammatory myopathies: a population-based case-control study.
      ,
      • Rider L.G.
      • Farhadi P.N.
      • Bayat N.
      • et al.
      Infections and medications associated with onset of myositis in myovision, a national myositis patient registry.
      ,
      • Giannini M.
      • Ohana M.
      • Nespola B.
      • et al.
      Similarities between COVID-19 and anti-MDA5 syndrome: what can we learn for better care?.
      ,
      • Balseiro A.
      • Oleaga A.
      • Polledo L.
      • et al.
      Clostridium sordellii in a Brown Bear (Ursus arctos) from Spain.
      The elevated risks of ASSD on exposure to pneumonia, of ILD in patients with IIM exposed to pneumonia, tuberculosis, or sarcoidosis observed, respectively, in 2 studies further support this hypothesis.
      • Rider L.G.
      • Farhadi P.N.
      • Bayat N.
      • et al.
      Infections and medications associated with onset of myositis in myovision, a national myositis patient registry.
      ,
      • Helmers S.B.
      • Jiang X.
      • Pettersson D.
      • et al.
      Inflammatory lung disease a potential risk factor for onset of idiopathic inflammatory myopathies: results from a pilot study.
      Molecular mimicry may be a mechanism involved in the onset of autoimmunity because shared epitope sequences have been observed between variola virus and tripartite motif-containing protein 3, which shared high sequence identity with TIF1γ,
      • Megremis S.
      • Walker T.D.J.
      • He X.
      • et al.
      Analysis of human total antibody repertoires in TIF1gamma autoantibody positive dermatomyositis.
      and between 3 immunogenic linear epitopes derived from patients with DM and SARS-CoV-2 proteins.
      • Megremis S.
      • Walker T.D.J.
      • He X.
      • et al.
      Antibodies against immunogenic epitopes with high sequence identity to SARS-CoV-2 in patients with autoimmune dermatomyositis.

      Medications

      Statin

      Statins are drugs widely used for reducing the risk of cardiovascular diseases by binding to 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) and thus interfering in the cholesterol biosynthesis. Discontinuation due to associated adverse events including muscle toxicity is common.
      • Zhu Y.
      • Chiang C.W.
      • Wang L.
      • et al.
      A multistate transition model for statin-induced myopathy and statin discontinuation.
      Statin-induced myopathy usually resolves after discontinuation but when the symptoms persist and require immunomodulatory treatment, statin-associated autoimmune IIM may have developed.
      • Christopher-Stine L.
      • Casciola-Rosen L.A.
      • Hong G.
      • et al.
      A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy.
      • Wu Y.F.
      • Lach B.
      • Provias J.P.
      • et al.
      Statin-associated Autoimmune Myopathies: A Pathophysiologic Spectrum.
      • Gonzales L.
      • Ali M.
      • Rodriguez-Cruz R.
      • et al.
      Statin-induced necrotizing autoimmune myopathy: A novel diagnosis requiring a more widespread recognition.
      • Hinschberger O.
      • Lohmann C.
      • Lannes B.
      • et al.
      [Immune-mediated necrotizing myopathy associated with antibodies to hydroxy-methyl-glutaryl-coenzyme A reductase].
      • Borges I.B.P.
      • Silva M.G.
      • Misse R.G.
      • et al.
      Lipid-lowering agent-triggered dermatomyositis and polymyositis: a case series and literature review.
      • Sailler L.
      • Pereira C.
      • Bagheri A.
      • et al.
      Increased exposure to statins in patients developing chronic muscle diseases: a 2-year retrospective study.
      • Keithler A.
      • Pomerantz B.
      • Trang D.N.
      • et al.
      Statin-induced necrotizing autoimmune myopathy: A case of delayed onset following statin discontinuation.
      • Caughey G.E.
      • Gabb G.M.
      • Ronson S.
      • et al.
      Association of Statin Exposure With Histologically Confirmed Idiopathic Inflammatory Myositis in an Australian Population.
      • John S.G.
      • Thorn J.
      • Sobonya R.
      Statins as a Potential Risk Factor for Autoimmune Diseases: A Case Report and Review.
      • Kanth R.
      • Shah M.S.
      • Flores R.M.
      Statin-associated polymyositis following omeprazole treatment.
      • Bae S.S.
      • Oganesian B.
      • Golub I.
      • et al.
      Statin use in patients with non-HMGCR idiopathic inflammatory myopathies: A retrospective study.
      • Machado H.
      • Andre A.
      • Félix A.
      • et al.
      Immune-mediated necrotizing myopathy associated with statin exposure: A rare side effect of a commonly used medication.
      Among all the IIM phenotypes, IMNM with anti-HMGCR autoantibodies is strongly related to statin exposure; up to 67% of patients from North America were exposed to statins before disease onset.
      • Christopher-Stine L.
      • Casciola-Rosen L.A.
      • Hong G.
      • et al.
      A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy.
      ,
      • Wu Y.F.
      • Lach B.
      • Provias J.P.
      • et al.
      Statin-associated Autoimmune Myopathies: A Pathophysiologic Spectrum.
      Moreover, compared with IMNM patients with anti-signal recognition particle autoantibodies, patients with anti-HMGCR autoantibodies were 33-fold more likely to have history of statin use.
      • Tiniakou E.
      • Pinal-Fernandez I.
      • Lloyd T.E.
      • et al.
      More severe disease and slower recovery in younger patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy.
      Unlike patients from North America, statin exposure in anti-HMGCR positive IMNM patients from eastern countries is much lower, ranging from 15% to 38%.
      • Watanabe Y.
      • Suzuki S.
      • Nishimura H.
      • et al.
      Statins and myotoxic effects associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies: an observational study in Japan.
      ,
      • Ge Y.
      • Lu X.
      • Peng Q.
      • et al.
      Clinical Characteristics of Anti-3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Antibodies in Chinese Patients with Idiopathic Inflammatory Myopathies.
      Because naturally occurring HMGCR inhibitors have been found in dietary products commonly used in eastern cuisine,
      • Wang T.H.
      • Lin T.F.
      Monascus rice products.
      ,
      • Lee J.-W.
      • Lee S.-M.
      • Gwak K.-S.
      • et al.
      Screening of edible mushrooms for the production of lovastatin and its HMG-CoA reductase inhibitory activity.
      this discrepancy may suggest an association between natural sources of HMGCR inhibitors and anti-HMGCR positive IMNM. Indeed, this assumption has been supported by 2 cases of statin naïve anti-HMGCR positive patients with consumption of shiitake mushroom and red rice, respectively.
      • Yoshida T.
      • Chikazawa H.
      • Kumon Y.
      • et al.
      Did Shiitake Mushrooms Induce Immune-Mediated Necrotizing Myopathy?.
      ,
      • Barbacki A.
      • Fallavollita S.A.
      • Karamchandani J.
      • et al.
      Immune-Mediated Necrotizing Myopathy and Dietary Sources of Statins.
      However, there is lack of supportive evidence from epidemiologic studies and the mechanisms of how these dietary compounds can inhibit the activity of HMGCR are unknown, similarly how they can lead to the production of anti-HMGCR autoantibodies.
      Statins may also be a risk factor for other IIM phenotypes, although evidence show weaker associations to other subsets than to IMNM. In a study exclusively including patients with DM or PM but not IMNM, the odds of regular statin use 6 months before disease onset in these patients was 6 times higher than the age-matched and sex-matched controls.
      • Sailler L.
      • Pereira C.
      • Bagheri A.
      • et al.
      Increased exposure to statins in patients developing chronic muscle diseases: a 2-year retrospective study.
      This finding was reproduced in a case-control study comparing patients with biopsy confirmed IIM excluding IMNM to age-matched and sex-matched controls, although the association was weaker than that observed in anti-HMGCR-positive patients.
      • Caughey G.E.
      • Gabb G.M.
      • Ronson S.
      • et al.
      Association of Statin Exposure With Histologically Confirmed Idiopathic Inflammatory Myositis in an Australian Population.
      ,
      • Tiniakou E.
      • Pinal-Fernandez I.
      • Lloyd T.E.
      • et al.
      More severe disease and slower recovery in younger patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy.
      Another case-control study reported that patients with DM and patients with PM were 2 times more likely to be exposed to statin use a year before disease diagnosis than patients with IBM after adjusting for age, gender, race, and year of diagnosis.
      • Rider L.G.
      • Farhadi P.N.
      • Bayat N.
      • et al.
      Infections and medications associated with onset of myositis in myovision, a national myositis patient registry.
      It has been suggested that statins contribute to the pathogenesis of IIM by upregulating HMGCR in regenerating muscle cells.
      • Mammen A.L.
      • Chung T.
      • Christopher-Stine L.
      • et al.
      Autoantibodies Against 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase in Patients With Statin-Associated Autoimmune Myopathy.
      If self-tolerance is lost to HMGCR, production of anti-HMGCR autoantibodies will be initiated, contributing to autoimmunity attacking muscle tissue. Individuals carrying the genetic variant HLA-DR11 may be more susceptible to this mechanism because this variant has been found to be strongly associated with statin-induced IMNM who are anti-HMGCR positive.
      • Limaye V.
      • Bundell C.
      • Hollingsworth P.
      • et al.
      Clinical and genetic associations of autoantibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase in patients with immune-mediated myositis and necrotizing myopathy.
      This evidence supports a role of the adaptive immune system in this subset of IIM. Other proinflammatory effects related to statins such as increased expression of major histocompatibility complex class I in myofibers may be involved in the disease development as well.
      • Christopher-Stine L.
      • Casciola-Rosen L.A.
      • Hong G.
      • et al.
      A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy.
      ,
      • Kanth R.
      • Shah M.S.
      • Flores R.M.
      Statin-associated polymyositis following omeprazole treatment.
      Little is known what nongenetic factors are related to statin-associated autoimmune IIM. Characteristics such as older age, female sex, chronic statin exposure, and comorbidities including Type 2 diabetes, hypertension, and hyperlipidemia have frequently been reported in cases of statin-associated autoimmune IIM.
      • Christopher-Stine L.
      • Casciola-Rosen L.A.
      • Hong G.
      • et al.
      A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy.
      • Wu Y.F.
      • Lach B.
      • Provias J.P.
      • et al.
      Statin-associated Autoimmune Myopathies: A Pathophysiologic Spectrum.
      • Gonzales L.
      • Ali M.
      • Rodriguez-Cruz R.
      • et al.
      Statin-induced necrotizing autoimmune myopathy: A novel diagnosis requiring a more widespread recognition.
      ,
      • Borges I.B.P.
      • Silva M.G.
      • Misse R.G.
      • et al.
      Lipid-lowering agent-triggered dermatomyositis and polymyositis: a case series and literature review.
      ,
      • Sailler L.
      • Pereira C.
      • Bagheri A.
      • et al.
      Increased exposure to statins in patients developing chronic muscle diseases: a 2-year retrospective study.
      ,
      • John S.G.
      • Thorn J.
      • Sobonya R.
      Statins as a Potential Risk Factor for Autoimmune Diseases: A Case Report and Review.
      ,
      • Machado H.
      • Andre A.
      • Félix A.
      • et al.
      Immune-mediated necrotizing myopathy associated with statin exposure: A rare side effect of a commonly used medication.
      ,
      • Close R.M.
      • Close L.M.
      • Galdun P.
      • et al.
      Potential implications of six American Indian patients with myopathy, statin exposure and anti-HMGCR antibodies.
      Interestingly, patients with prior exposure to simvastatin or pravastatin were at higher risk of having chronic muscular diseases including DM and PM than patients exposed to atorvastatin or fluvastatin but the associations were not statistically significant.
      • Sailler L.
      • Pereira C.
      • Bagheri A.
      • et al.
      Increased exposure to statins in patients developing chronic muscle diseases: a 2-year retrospective study.
      Significant interaction between statins and proton pump inhibitors was also found when estimating the odds ratio of statin-associated DM or PM.
      • Sailler L.
      • Pereira C.
      • Bagheri A.
      • et al.
      Increased exposure to statins in patients developing chronic muscle diseases: a 2-year retrospective study.
      The association between statins and IMNM has led to a safety concern about statin use in patients with IIM for cardiovascular disease prevention. Although evidence is sparse, a study observed that 22 out of 23 patients with non-HMGCR IIM tolerated statins well.
      • Bae S.S.
      • Oganesian B.
      • Golub I.
      • et al.
      Statin use in patients with non-HMGCR idiopathic inflammatory myopathies: A retrospective study.

      Immune checkpoint inhibitors

      Immune checkpoint inhibitors (ICIs) are a group of medications that have revolutionized cancer treatment in recent years. Because they interfere with immune pathways, they have been associated with rheumatic immune-related adverse events, for example, myositis. Symptoms typically occur shortly after monotherapy or combination therapy with programmed death (PD)-1/PD-ligand 1 inhibitor or/and cytotoxic T lymphocyte antigen-4 inhibitor.
      • Aldrich J.
      • Pundole X.
      • Tummala S.
      • et al.
      Inflammatory Myositis in Cancer Patients Receiving Immune Checkpoint Inhibitors.
      • Xu M.
      • Nie Y.
      • Yang Y.
      • et al.
      Risk of Neurological Toxicities Following the Use of Different Immune Checkpoint Inhibitor Regimens in Solid Tumors: A Systematic Review and Meta-analysis.
      • Moreira A.
      • Loquai C.
      • Pföhler C.
      • et al.
      Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors.
      • Anquetil C.
      • Salem J.E.
      • Lebrun-Vignes B.
      • et al.
      Immune Checkpoint Inhibitor-Associated Myositis: Expanding the Spectrum of Cardiac Complications of the Immunotherapy Revolution.
      The pathogenesis of ICI-associated myositis is not well-understood but enhanced activation of T cells may partially explain the phenomenon because antigen-specific T cells play an important role in IIM development.
      • Lundberg I.E.
      • Fujimoto M.
      • Vencovsky J.
      • et al.
      Idiopathic inflammatory myopathies.
      ,
      • Okiyama N.
      • Ichimura Y.
      • Shobo M.
      • et al.
      Immune response to dermatomyositis-specific autoantigen, transcriptional intermediary factor 1gamma can result in experimental myositis.
      Importantly, even though lymphocytic infiltration is presented in muscle biopsy of patients with ICI-associated myositis,
      • Aldrich J.
      • Pundole X.
      • Tummala S.
      • et al.
      Inflammatory Myositis in Cancer Patients Receiving Immune Checkpoint Inhibitors.
      characteristics such as concurrence with myasthenia gravis or myocarditis, infrequent positivity of MSAs/MAAs, high mortality, and resolution after steroid and intravenous immunoglobin treatments highlight a distinct pathologic mechanism different from that of IIM.
      • Aldrich J.
      • Pundole X.
      • Tummala S.
      • et al.
      Inflammatory Myositis in Cancer Patients Receiving Immune Checkpoint Inhibitors.
      ,
      • Moreira A.
      • Loquai C.
      • Pföhler C.
      • et al.
      Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors.
      ,
      • Anquetil C.
      • Salem J.E.
      • Lebrun-Vignes B.
      • et al.
      Immune Checkpoint Inhibitor-Associated Myositis: Expanding the Spectrum of Cardiac Complications of the Immunotherapy Revolution.

      Vitamin D Deficiency

      Vitamin D deficiency has been suggested as a risk factor for adult IIM. Previous evidence has shown that vitamin D deficiency was not only more commonly seen in patients with newly diagnosed IIM than matched controls; it was also correlated with elevated muscle enzymes, increased number of proinflammatory cells, as well as anti-Jo1 and anti-Mi2 autoantibodies in newly diagnosed and untreated patients with IIM.
      • Yu Z.
      • Cheng H.
      • Liang Y.
      • et al.
      Decreased Serum 25-(OH)-D Level Associated With Muscle Enzyme and Myositis Specific Autoantibodies in Patients With Idiopathic Inflammatory Myopathy.
      ,
      • Azali P.
      • Helmers S.B.
      • Kockum I.
      • et al.
      Low serum levels of vitamin D in idiopathic inflammatory myopathies.
      Heliotrope rash, gastrointestinal and liver involvements were also frequently seen in patients with IIM with extremely low levels of vitamin D at diagnosis.
      • Yu Z.
      • Cheng H.
      • Liang Y.
      • et al.
      Decreased Serum 25-(OH)-D Level Associated With Muscle Enzyme and Myositis Specific Autoantibodies in Patients With Idiopathic Inflammatory Myopathy.
      Interestingly, vitamin D receptor polymorphisms associated with IIM have been suggested but these findings are inconsistent.
      • Dzhebir G.
      • Kamenarska Z.
      • Hristova M.
      • et al.
      Association of vitamin D receptor gene BsmI B/b and FokI F/f polymorphisms with adult dermatomyositis and systemic lupus erythematosus.
      ,
      • Bodoki L.
      • Chen J.Q.
      • Zeher M.
      • et al.
      Vitamin D receptor gene polymorphisms and haplotypes in Hungarian patients with idiopathic inflammatory myopathy.
      Given that only one time-point measurement of vitamin D was analyzed and that the observed low level at IIM diagnosis can be due to less outdoor activity because of muscle weakness, it remains unclear if vitamin D deficiency is causally associated with IIM.

      Summary

      In this review, we have discussed several suggested environmental factors and their influence on clinically or serologically defined IIM phenotypes. This knowledge provides important clues to infer into the pathogenic mechanisms of IIM. Importantly, there is a growing body of evidence implicating lungs as the initial site of autoimmunity, which later may lead to the onset of some subsets of IIM in particular those with ILD.
      • Notarnicola A.
      • Preger C.
      • Lundström S.
      • et al.
      Longitudinal assessment of reactivity and affinity profile of anti-Jo1 autoantibodies to distinct HisRS domains and a splice variant in a cohort of patients with myositis and anti-synthetase syndrome.
      ,
      • Galindo-Feria A.S.
      • Albrecht I.
      • Fernandes-Cerqueira C.
      • et al.
      Proinflammatory Histidyl-Transfer RNA Synthetase-Specific CD4+ T Cells in the Blood and Lungs of Patients With Idiopathic Inflammatory Myopathies.
      As presented above, many of the external environmental factors suggested as risk factors for IIM, including smoking, occupational pollutants, and infectious agents, are associated with the subtype ASSD, IIM-associated ILD, or the presence of either anti-Jo1 or anti-MDA5 autoantibodies,
      • Ying D.V.
      • Schmajuk G.
      • Trupin L.
      • et al.
      Inorganic Dust Exposure During Military Service as a Predictor of Rheumatoid Arthritis and Other Autoimmune Conditions.
      ,
      • Pipis N.
      • Rothwell S.
      • Cooper R.
      • et al.
      Gene-Environmental Interaction of HLA-DRB1∗03:01 and Smoking for the Development of Anti-Jo-1 Autoantibodies in Idiopathic Inflammatory Myopathies: A UK Study.
      ,
      • Rider L.G.
      • Farhadi P.N.
      • Bayat N.
      • et al.
      Infections and medications associated with onset of myositis in myovision, a national myositis patient registry.
      ,
      • Helmers S.B.
      • Jiang X.
      • Pettersson D.
      • et al.
      Inflammatory lung disease a potential risk factor for onset of idiopathic inflammatory myopathies: results from a pilot study.
      ,
      • Chen H.H.
      • Yong Y.M.
      • Lin C.H.
      • et al.
      Air pollutants and development of interstitial lung disease in patients with connective tissue disease: a population-based case-control study in Taiwan.
      which are features of lung involvement in IIM. These observations further support that autoimmunity of IIM may first take place in lungs in response to environmental insults in susceptible individuals. Furthermore, the links to specific MSAs provide insight into the site of antigen presentation and production of autoantibodies, as seen in anti-Jo1, anti-Mi2, and anti-HMGCR autoantibodies.
      • Burd C.J.
      • Kinyamu H.K.
      • Miller F.W.
      • et al.
      UV Radiation Regulates Mi-2 through Protein Translation and Stability.
      ,
      • Mammen A.L.
      • Chung T.
      • Christopher-Stine L.
      • et al.
      Autoantibodies Against 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase in Patients With Statin-Associated Autoimmune Myopathy.
      ,
      • Levine S.M.
      • Raben N.
      • Xie D.
      • et al.
      Novel conformation of histidyl-transfer RNA synthetase in the lung: the target tissue in Jo-1 autoantibody-associated myositis.
      The dose-dependent manners of correlations found in smoking, occupational dust, infections, and vitamin D deficiency suggest proportional correlations between accumulation of environmental exposure and IIM onset.
      • Ying D.V.
      • Schmajuk G.
      • Trupin L.
      • et al.
      Inorganic Dust Exposure During Military Service as a Predictor of Rheumatoid Arthritis and Other Autoimmune Conditions.
      ,
      • Nielsen P.R.
      • Kragstrup T.W.
      • Deleuran B.W.
      • et al.
      Infections as risk factor for autoimmune diseases - A nationwide study.
      ,
      • Schiffenbauer A.
      • Faghihi-Kashani S.
      • O'Hanlon T.P.
      • et al.
      The effect of cigarette smoking on the clinical and serological phenotypes of polymyositis and dermatomyositis.
      ,
      • Yu Z.
      • Cheng H.
      • Liang Y.
      • et al.
      Decreased Serum 25-(OH)-D Level Associated With Muscle Enzyme and Myositis Specific Autoantibodies in Patients With Idiopathic Inflammatory Myopathy.
      Besides pathogenic implications, information on environmental factors for IIM and IIM-related complications is useful for disease prevention and management.

      Future directions

      Although several attempts have been made to identify potential environmental factors associated with IIM, no causal relationship has been established for a single factor. Given the fact that IIM is a complex and rare disease, this is not surprising. Small sample size, lack of valid and longitudinal data on environmental exposure and potential confounders, as well as lack of proper control groups, confounding adjustment, and analysis by serologic profile are common limitations of many of the previously published studies, and these also reflect the challenges for future studies. It is impossible to overcome all these limitations in one study but establishing international collaborations to increase sample size and data diversity, and to enable standardized data collection and proper selection of controls is crucial to explore the role of environmental factors in the development of IIM. Moreover, although the pathogenesis of IIM is multifactorial, it is interesting that previous studies seldom considered interactions between environmental factors or between environmental and genetic factors. There is also a lack of mechanistic studies exploring the role of environmental factors for IIM at molecular level. Future epidemiologic and basic science studies should focus on answering these questions.

      Clinics care points

      • Little is currently known about the clinical relevance of avoiding the suggested environmental triggers in patients with idiopathic inflammatory myopathies (IIMs). However, in clinical practice, patients with dermatomyositis are recommended to protect skin from sun exposure.
      • Although smoking cessation is recommended for general long-term health benefits, we suggest all providers counsel patients on smoking cessation after IIM diagnosis.
      • Current evidence suggests that statin use as secondary cardiovascular prophylaxis is safe and tolerable for patients with non-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase IIM.

      Acknowledgments

      This article was supported by grants from The Swedish Research Council No 2020-01378 , the Swedish Rheumatism Association , King Gustaf V 80 Year Foundation , Stockholm Regional Council (ALF), and Heart and Lung foundation .

      Disclosure

      Dr I.E. Lundberg has received consulting fees from Corbus Pharmaceuticals, Inc and research grants from AstraZeneca and has been serving on the advisory board for Astra Zeneca, Bristol Myers Squibb, EMD Serono Research & Development Institute, Argenx, Octapharma, Kezaar, Orphazyme, Pfizer and Janssen and has stock shares in Roche and Novartis. The other authors declare no conflicts of interest.

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