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Supplementary Table 1 | Potential issues regarding prevention of ARDs Issue Discussion Understanding of the natural history of These issues could be evaluated through natural history studies of ARDs must be sufficient to enable preclinical ARDs that target high-risk populations, such as relatives accurate prediction of future disease in of patients with established disease or cohorts of high-risk each individual (that is, personalized individuals identified through broad population screening for genetic medicine), and to identify therapeutic factors or expression of biomarkers that are enriched in prevalent targets for prevention of disease and incident autoimmunity and clinically apparent diseaseS1,S2,S3 development What should be included in prediction In terms of clinical trial design, prediction models would probably models for disease? need to identify individuals who are likely to develop clinically apparent disease in a relatively short period of time (or ‘imminent’ disease) to enable completion of studies within a defined time period What are appropriate public-health Individuals who are at-risk of future ARDs could be identified efforts to identify individuals at-risk of through broad public-health efforts used in diseases such as cancer ARDs in whom disease prevention would or heart disease, or by targeting high-risk populations, such as be reasonable approach? family members of patients with disease, individuals from populations with increased risk of disease (for example, American Indians), or individuals identified through screening mechanisms who have high-risk genetic (for example, shared epitope) and/or environmental exposures (for example, smokers or those with certain infections) The cost-effectiveness of preventing ARDs needs to be evaluated, including analyses of the costs of identifying at-risk individuals, the possibility of treating individuals who have markers of potentially increased risk of ARDs, but never develop clinically apparent disease, and the potential future benefits and adverse effects of treatment How high should the likelihood of future Lifestyle intervention (for example, smoking cessation) might be an ARD be before initiating preventive acceptable approach in many individuals with even a relatively low therapy? risk of future ARD; however, high-risk pharmacologic therapy will probably require a higher likelihood of disease development to be justified What will individuals who are at-risk of a Answering this question will require determination of what level of future ARD be willing to undergo for risk an individual would need to be presented with before they prevention? agree to undergo therapy Published work suggests that relatives of patients with RA would be willing to participate in a pharmacologic prevention trial if their risk for RA was >30% within 5 yearsS4 Is intervention worthwhile in individuals Autoimmunity might not be benign, even if classic manifestations of with autoimmunity, even if they have tissue injury, such as synovitis in RA, are not present; for example, low risk of progression to a clinically emerging data suggesting that autoantibodies might be associated apparent ARD? with an increased CVD riskS5 At what point in preclinical autoimmunity Attempts to halt autoimmunity might be more successful if is it most reasonable to intervene? intervention occurs very early in the disease process, before a possible transition from ‘benign’ to ‘pathogenic’ autoimmunity; however, the clinical benefit of early intervention could take years to identify Intervention in late preclinical disease might already be too late to effectively halt/abrogate autoimmunity What pharmacological agent or other Deciding which pharmacological agent is appropriate requires an intervention that will adequately understanding of relevant biologic pathways for disease prevention, abrogate disease in its preclinical phase and balancing of the probably risks and benefits of the preventive is appropriate to use in individuals intervention/agent in each individual without clinical disease? What do we hope to achieve with Whether resetting of the immune system and drug-free remission is preventive interventions and are possible in patients with ARD remains unknown adequate measures in place to measure The acceptability of early initiation of immunomodulation to prevent such responses to a preventive tissue damage, even if the immunomodulatory agent must be used intervention? indefinitely to maintain control of autoimmunity and prevention of clinical manifestations of disease, must also be determined Established measures of disease activity have not been well tested Other considerations in preclinical disease, thus, relevant outcomes measures must be developed if preventive interventions are implemented in individuals with minimal or absent symptoms; we must determine whether changes in biomarkers alone can be used as outcomes, or whether clinically defined end points be the gold standard for prevention studies Given effective treatments are available for most ARDs, withholding treatment until clear disease is present might be more ethical than risking over-treating an individual with autoimmunity who might never develop clinically meaningful disease; however, this standpoint must be justified based on the results of future studies Strategies to identify individuals at high-risk of future disease might also lead to more rigorous clinical follow-up and early treatment that is beneficial, even if prevention strategies do not exist; however, an important consideration is whether screening programmes that identify individuals who are potentially susceptibly to ARDs will affect their ability to purchase health insurance coverage Supplementary references: S1. El-Gabalawy, H. S. et al. Familial clustering of the serum cytokine profile in the relatives of rheumatoid arthritis patients. Arthritis Rheum. 64, 1720–1729 (2012). S2. Bos, W. H. et al. Arthritis development in patients with arthralgia is strongly associated with anti-citrullinated protein antibody status: a prospective cohort study. Ann. Rheum. Dis. 69, 490–494 (2010). S3. Kolfenbach, J. R. et al. A prospective approach to investigating the natural history of preclinical rheumatoid arthritis (RA) using first-degree relatives of probands with RA. Arthritis Rheum. 61, 1735–1742 (2009). S4. Novotny, F., Haeny, S., Hudelson, P., Escher, M. & Finckh, A. Primary prevention of rheumatoid arthritis: a qualitative study in a high-risk population. Joint Bone Spine 80, 673–674 (2013). S5. Agmon-Levin, N. & Selmi, C. The autoimmune side of heart and lung diseases. Clin. Rev. Allergy Immunol. 44, 1–5 (2013).