Environmental Factors in the Pathogenesis of Systemic Autoimmune Diseases

1. Environmental Factors in the Pathogenesis of Systemic Autoimmune Diseases Collaborative on Health & the EnvironmentJuly 2008 Frederick W. Miller, M.D., Ph.D. Chief, Environmental Autoimmunity Group NIEHS Office of Clinical Research, NIH, DHHS Bethesda, MD 20892 Email: millerf@mail.nih.gov

2. Evidence for Environmental Influences in the Pathogenesis of Autoimmune Diseases • Strong temporal associations with some environmental exposures and disease onset • Dechallenge = disease improvement after agent removal • Rechallenge = disease recurrence after agent re-exposure • Less than 50% disease concordance in monozygotic twins • Geographic clustering in disease incidence or prevalence • Changes in the prevalence or incidence of disease over time • Seasonality in disease birth dates and disease onset • Strong biologic plausibility from animal models • Epidemiologic associations between particular exposures and certain diseases Cooper and Miller 2007 Immunotoxicology and Immunopharmacology

3. Genetic Risk Factors for Environmentally Associated Immune-mediated Diseases

4. Possible Gene-Environment Interactions Resulting in Autoimmune Disorders Gourley and Miller 2007 Nature Clin Prac Rheum

5. EARD SG Proposed Stages in the Definition of an Environmental Disease • STAGE 1 -Case reports, defined by ascertainment criteria, propose a possible association of a specific clinical syndrome with a given exposure (eosinophilia and myalgia following L-tryptophan ingestion) • STAGE 2 –After such cases are reported, surveillance criteria are proposed and epidemiologic and laboratory studies test hypotheses (eosinophilia-myalgia syndrome) • STAGE 3 -If studies above are positive, specific classification and other criteria are defined for that specific environmental disease (LT-associated EMS) • STAGE 4 - Criteria are reassessed and refined as additional data are obtained about the disease Miller et al. 2000 Arthritis & Rheum

6. Possible Environmental Triggers of Autoimmune Diseases • Infectious agents • Bacteria / parasites: Streptococci, Borrelia, others • Viruses: +RNA, DNA, retroviruses, others • Non-infectious agents • Drugs: D-penicillamine, hydralazine, many others • Biologics: Vaccines, cytokines, others • Foods: L-tryptophan, adulterated rapeseed oil • Medical devices: Collagen and silicone implants • Occupational exposures: Silica, beryllium, vinyl chloride • Other exposures: tobacco smoke, UV light, mercury, petrochemicals, stress, others

7. Possible Mechanisms by which Environmental Agents may Induce Autoimmune Disease • Alteration of target tissue autoantigen structure • Upregulation or altered locations of target tissue expression of autoantigens • Cytotoxic, inhibitory, or stimulatory effects on components of the immune system • Molecular mimicry – structures shared between environmental agent and self • Other effects and combinations of the above - different pathogenic mechanisms are likely at work in different syndromes

8. Epidemiology of Environmental Exposures and RA Odds Ratio or Relative Risk Exposure Comments (95% CI) Crystalline silica - Swedish study – exposed men - US National Occupational Mortality Surveillance Study Diet - Nested case control - Meat and meat products combined - Total protein Mineral oil - Swedish study, 1,419 cases, male-only association Pesticides - US study, 135 cases, mixing or applying Smoking - Swedish, population based case-control - Single SE, +RF, never smoked - No SE, +RF, ever smoked - Single SE, +RF, currently smoke - Double SE, +RF, currently smoke Solvents - US Agricultural Health Study, 135 cases UV light - UV exposure of 6 hours/day Vitamin D - Prospective cohort, 152 cases, high vs. low EBV - Antibodies to antiviral citrullinated peptide, 300 cases Parvovirus B19 - B19 DNA in synovium - IgM to B19 >6 months duration - JRA, 76 discordant monozygotic twins, IgG to B19 0.1 1.0 10 100 Gourley and Miller 2007 Nature Clin Prac Rheum

9. Environmental Exposures and Systemic Sclerosis Odds Ratio or Relative Risk Exposure Comments (95% CI) Crystalline silica - US National Occupational Mortality Surveillance Study – ever exposure - Italian study, 55 selected cases - French study, 80 consecutive cases Fumes - French study, 80 consecutive cases Solvents - Italian study, 55 selected cases - French study, 80 consecutive cases - Italian study, organic solvents - UK study, organic solvents - South Carolina study, men-only association 0.1 1.0 10 100 Gourley and Miller 2007 Nature Clin Prac Rheum

10. Epidemiology of Environmental Exposures and Myositis Odds Ratio or Relative Risk Exposure Comments (95% CI) Parvovirus - No association with IgG to B19 URI (one year prior) - Questionnaire, case – sibling control Streptococci - Case review(household exposure) Exertion - Case – sibling control, 104 cases Collagen Implants - Cohort study - standardized incidence ratio Vaccinations - Case control, 322 cases - Any vaccine one year prior to diagnosis - Influenza vaccination 0.1 1.0 10 100 Gourley and Miller 2007 Nature Clin Prac Rheum

11. Expanded Environmental Scans? • Just as whole genome scans have revolutionized our thinking of genetic risk factors for disease, the possibility of expanded environmental scans could revolutionize our capacity to define environmental risk factors in the future • New exposure assessment technologies and validated biomarkers of exposure are needed • Could begin by integrating validated exposure questionnaires with systems biology biomarkers for exposures from RNA expression signatures, proteomic and metabolomic analyses and with antibody microarrays to capture the immune memory of a lifetime of exposures

12. Studies of environmental risk factors for autoimmunity are in their infancy and need to be greatly expanded given the apparent autoimmunity epidemic • Challenges include: • The rarity, heterogeneity and multifactorial nature of many diseases • Suboptimal coordination among nations, agencies and researchers • Inadequate validated exposure assessment tools and training • Limited population-based incidence, prevalence, demographic information and phenotype databases for most diseases • The advances in novel technologies, statistical approaches and development of collaborating consortia and focused resources - which have resulted in the recent explosion of genetic information on many complex diseases - now need to be applied to environmental studies so that we can eventually interrupt pathogenesis before the onset of illness and transform the practice of medicine from curative to preemptive paradigms. Summary – Environmental Aspects of Systemic Autoimmune Diseases