Enhancing NIH Research on Autoimmune Disease (2022)

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1 Introduction Autoimmune diseases occur when the body’s immune system, which normally defends the body against disease and infection, malfunctions and mistakenly attacks healthy cells, tissues, and organs (NIEHS, 2021). These attacks can affect any part of the body and damage may target a specific organ system or be systemic (Fridkis-Hareli, 2008). For some dis- eases, diagnosis can be problematic; people can experience symptoms and accrue tissue damage for years and consult multiple physicians before receiving a correct diagnosis (Arbuckle et al., 2003; Calabrese et al., 2021; Dall’Era, 2013). Pain is a common symptom, and nerve dysfunction can amplify pain sensations (Mifflin and Kerr, 2017). People with autoimmune diseases commonly develop more than one autoimmune disease (Cojo- caru et al., 2010; Rojas-Villarraga et al., 2012), and they can be at increased risk of developing cancer (Franks and Slansky, 2012) and cardiovascular disease (Williams et al., 2019) among other comorbidities and complica- tions. Autoimmune diseases are chronic, lifelong, and can cause signifi- cant physical and psychosocial impairment, impeding activities of daily living, productivity, and quality of life. In children, autoimmune diseases can cause irreversible organ damage at an early age and adversely affect growth and development, with lasting effects into adulthood (Amaro and Chiarelli, 2020; Cirillo et al., 2017; Groot et al., 2019; Heshin-Bekenstein et al., 2018; Lim et al., 2013; Lim et al., 2017; Mauras et al., 2021; Mitchell, 2017; Ruano et al., 2018). Autoimmune disease can also be fatal; uncon- trolled type 1 diabetes is well-known to be life-threatening (Reno et al., 2018), a 2018 study determined systemic lupus erythematosus to be a 17 PREPUBLICATION COPY—Uncorrected Proofs 

18 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE leading cause of death in young females in the United States (Yen and Singh, 2018), and autoimmune diseases as a group rank among the ten leading causes of death for females (Thomas et al., 2010; Walsh and Rau, 2000). There are no known cures for autoimmune diseases. There is limited data on the incidence and prevalence of autoimmune diseases. In 2005, the National Institutes of Health (NIH) Autoimmune Diseases Coordinating Committee (ADCC)1 estimated that autoimmune diseases affect 14.7 to 23.5 million people in the United States (ADCC, 2005). More recent epidemiologic data are inadequate to provide an updated estimate of the U.S. prevalence of autoimmune diseases, but the number is likely higher given the increase in the U.S. population (United States Census Bureau, 2021) and that the prevalence of some autoimmune diseases and autoantibodies appears to be growing (Dinse et al., 2020; Mayer-Davis et al., 2017; Shivashankar et al., 2017). The personal and soci- etal costs of autoimmune diseases are substantial but difficult to estimate overall, since costs are attributed mostly to specific diagnoses and because calculations of acute care costs, medications, hospitalizations, and annual or lifetime costs, for example, are not standardized across autoimmune diseases (AARDA and NCAPG, 2011). NIH, the U.S. federal agency primarily responsible for sponsoring and conducting biomedical research, supports research on autoimmune disease.2 NIH’s stated mission is to “seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and dis- ability” (NIH, 2017). The agency conducts its mission and goals through a complex and multidisciplinary structure of 27 Institutes and Centers (ICs), each focusing on different areas of biomedical research. The Office of the Director sets policies and coordinates the activities of the ICs. Autoim- mune disease research activities occur across the ICs through both extra- mural and intramural research activities. In fiscal year 2020, NIH’s budget obligations3 were approximately $41.5 billion, of which NIH spent $1.1 1 NIH established the ADCC in 1998 in response to Congressional encouragement to facilitate coordination of autoimmune disease research across the National Institutes of Health (NIH), federal agencies, professional societies, and patient and advocacy organiza- tions (NIAID, 2021). 2 NIH is one of the 11 operating divisions in the U.S. Department of Health and Human Services (HHS, 2022). The other 10 operating divisions are: Administration for Children and Families (ACF), Administration for Community Living (ACL), Agency for Healthcare Research and Quality (AHRQ), Agency for Toxic Substances and Disease Registry (ATSDR), Centers for Disease Control and Prevention (CDC), Centers for Medicare & Medicaid Ser- vices (CMS), Food and Drug Administration (FDA), Health Resources and Services Admin- istration (HRSA), Indian Health Service (IHS), and Substance Abuse and Mental Health Services Administration (SAMHSA). 3 Actual total obligations. PREPUBLICATION COPY—Uncorrected Proofs 

INTRODUCTION 19 billion, or 2.6 percent of the NIH obligations, supporting autoimmune disease research (NIH, 2020, 2021). In language supporting the Further Consolidated Appropriations Act, 2020,4 Congress noted that autoimmune diseases affect an estimated 5 to 7 percent of Americans; that these diseases are more common in women than men; and that many women with one autoimmune disease have a second autoimmune disease or other condition. That language also stated that “there is no single office within National Institutes of Health tasked with coordinating research across the agency or examining the complex interplay among these diseases and conditions,” and it called for NIH to contract with the National Academies of Sciences, Engineering, and Medi- cine (National Academies) to identify and review NIH’s research efforts in this broad area. In response, the National Academies convened the Com- mittee for the Assessment of NIH Research on Autoimmune Diseases (the committee) to respond to this request. The 13-member interdisciplinary committee comprises experts in autoimmune diseases, immunology, epi- demiology, environmental health, neurology, nephrology, gastroenterol- ogy, cardiology, psychiatry, rheumatology, disability, pediatrics, women’s health, sex differences research, health disparities research, and research administration. One member of the committee has had multiple sclerosis for years, providing insight into the lived experience of having an auto- immune disease. More information about the committee members can be found in Appendix A. Charge to the Committee The Statement of Task guiding this study charged the committee to assess NIH research activities on autoimmune diseases with a particu- lar emphasis on the risk factors, diagnostic tools, barriers to diagnoses, treatments, and prospects for cures. The committee’s task also included considering the occurrence of multiple autoimmune diseases and the interplay of the diseases with comorbidities, as well as identifying bar- riers to NIH-sponsored research, research gaps, and promising areas for future NIH-sponsored research that would benefit the greatest need. Box 1-1 provides the committee’s Statement of Task. Committee’s Approach For the purpose of this report, the committee’s review of NIH autoim- mune disease research funding focused on a select number of autoimmune 4 Further Consolidated Appropriations Act, H.R.1865, 116th Cong., 1st sess., Congressional Record 165, no. 204, daily ed. (December 17, 2019): H11071. PREPUBLICATION COPY—Uncorrected Proofs 

20 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE BOX 1-1 Statement of Task The National Academies of Sciences, Engineering, and Medicine will convene an ad hoc committee to conduct a congressionally mandated study of NIH re- search on autoimmune diseases. The study will: • Provide a general overview (with particular focus on NIH research efforts) of epidemiologic trends in autoimmune diseases. • For common autoimmune diseases (including those that are overrepresent- ed in women), evaluate the NIH research portfolio with particular attention to issues such as risk factors; diagnostic tools; barriers to diagnoses; treatments; and prospects for cures. • Review  NIH’s research activities related to specific  autoimmune  diseas- es, the occurrence of multiple autoimmune diseases in individuals, and the interplay of autoimmune diseases and comorbidities. • Assess trends in the focus of NIH research and address whether the trends are reflective of the changes in epidemiology as compared to other factors such as availability of research tools and technologies, and emerging bio- medical knowledge and concepts. • Identify barriers to NIH-sponsored research and research gaps for autoim- mune diseases. • Identify promising areas for future NIH-sponsored research for autoim- mune diseases that would benefit the greatest need. • Evaluate Institute and Center structure in support of NIH autoimmune disease research to identify where needs are met and where coordination could be enhanced. • Produce  and  publish  a final consensus committee report summarizing the committee’s findings, conclusions, and recommendations. The report must address NIH accomplishments, challenges that NIH faces, as well as pos- sible solutions to the challenges. conditions over a select period of time. The committee notes that there is no consensus definition of autoimmune disease, nor is there a standard list of autoimmune diseases, though the National Institute of Allergy and Infectious Diseases (NIAID) identifies more than 80 autoimmune diseases (NIAID, 2017). In addition, the Autoimmune Registry5 and the Auto- immune Association (formerly named American Autoimmune Related 5 The Autoimmune Registry, Inc.is a non-profit organization that serves as a hub for re- search, statistics, and patient data on all autoimmune disease (Autoimmune Registry Inc., 2021). PREPUBLICATION COPY—Uncorrected Proofs 

INTRODUCTION 21 Diseases Association, or AARDA)6 compiled two longer lists of autoim- mune diseases that include 147 and 150 diseases, respectively (Autoim- mune Association, 2021b; Autoimmune Registry Inc., 2020). Appendix B lists the diseases the Autoimmune Association identifies as autoim- mune diseases. The committee acknowledged that given the timeframe it had to conduct its work, it would be unable to examine a large set of autoimmune diseases. As an initial step in selecting a set of diseases, the committee cross-referenced the Autoimmune Association list of diseases with the list of diseases that the Autoimmune Registry designates as hav- ing “strong” evidence for being autoimmune diseases. The committee deemed the resulting list to be a reasonable starting point from which to choose. Autoimmune Diseases of Focus A number of factors contributed to the committee’s selection of auto- immune diseases. Box 1-2 lists these factors, and Table 1-1 lists the dis- eases the committee selected. The committee acknowledges that there are autoimmune diseases that are more rare than the diseases it selected for special focus, but the committee believes that including rare diseases could have diminished its ability to answer the questions with which it had been tasked. BOX 1-2 Factors Considered in Selecting Diseases for Special Focus • Autoimmune diseases identified in Congressional Record H11061-01, 2019. • Diseases overrepresented in women. • Diseases that may affect multiple systems and are associated with comorbidities.1 • Diseases that illustrate the spectrum of autoimmune disease. • Availability of NIH data on research funding for the disease. 1 More granular definitions of coexisting disease (comorbidity, complication, co-occurring autoimmune disease, and overlapping autoimmune disease) are provided in Chapter 2. 6 The Autoimmune Association (previously known as the American Association of Au- toimmune Related Disorders (AARDA)) is a non-profit organization focused on the eradi- cation of autoimmune diseases and impact of autoimmunity (Autoimmune Association, 2021a). PREPUBLICATION COPY—Uncorrected Proofs 

22 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE TABLE 1-1  Disease Selection Considerations Included in Further Consolidated RCDCb Prominent Appropriations Spending Additional in Women Act, 2020a Category Considerations Comorbid with other autoim- mune conditions; relatively Sjögren’s Disease X older onset; difficult to diagnose Systemic Lupus Early adulthood onset; popu- X X X Erythematosus lation disparities Closely related to systemic Antiphospho- lupus erythematosus; particu- X lipid Syndrome larly prominent for pregnancy risk Rheumatoid X X X High prevalence Arthritis Psoriasis X High prevalence High prevalence; comorbid Inflammatory extra-intestinal manifesta- X X X Bowel Diseasec tions; onset at a relatively early age Celiac Disease X X High prevalence Primary Biliary X Population disparities Cholangitis Comorbid with other autoim- Multiple Scle- X X X mune conditions; population rosis disparities Acute mortality risk; rela- Type 1 Diabetes X tively young onset Autoimmune X High prevalence Thyroid Disease a Further Consolidated Appropriations Act, H.R.1865, 116th Cong., 1st sess., Congressional Record 165, no. 204, daily ed. (December 17, 2019): H11071. b RCDC is the NIH Research, Condition, and Disease Categorization system. c Includes Crohn’s disease and ulcerative colitis. PREPUBLICATION COPY—Uncorrected Proofs 

INTRODUCTION 23 Autoimmune Diseases Identified in Congressional Record and Overrepresentation of Women The language supporting the call for the National Academies study specifically noted the following autoimmune diseases: rheumatoid arthri- tis, multiple sclerosis, lupus, celiac disease, inflammatory bowel disease, and type 1 diabetes. The congressional language also included a reference to the 2010 National Academies study Women’s Health Research: Prog- ress, Pitfalls, and Promise that identified autoimmune conditions as “the leading cause of morbidity in women, and they affect women’s quality of life greatly” (IOM, 2010). The Statement of Task does not direct the committee to focus exclusively on women’s health, but it does direct the committee to examine “common autoimmune diseases (including those overrepresented in women).” The committee decided to include the six diseases identified in the congressional language along with Sjögren’s disease (sometimes called Sjögren’s syndrome), psoriasis, antiphospho- lipid syndrome, primary biliary cholangitis, and autoimmune thyroid disease, each of which also affects more women than men. The commit- tee notes that while many autoimmune diseases do occur predominantly in women, multiple other patterns occur across autoimmune diseases in relation to age, sex, race and ethnicity, and social determinants. Variations also exist in other dimensions of autoimmune disease, including progres- sion of disease and outcomes. Diseases That May Encompass Multiple Systems and Comorbidities. Unlike many other illnesses, autoimmune diseases affect multiple organ systems (for instance, skin, kidney, lung, joints, and brain), some- times leading to different manifestations with different names. Many autoimmune diseases overlap; for example, features of Sjögren’s disease or Hashimoto’s thyroiditis (also called Hashimoto’s disease) often accom- pany rheumatoid arthritis, systemic lupus erythematous, and related ill- nesses. There is little consensus whether such patients have one or several autoimmune diseases. Diseases That Collectively Illustrate the Spectrum of Autoimmune Diseases The committee sought to select diseases that could illustrate the spec- trum of autoimmune disease, which is diverse in organ systems affected, disease course, patient population, time of onset, and severity, among other factors. For example, type 1 diabetes is a disease that most often arises in children, adolescents, and young adults, while systemic lupus erythematous usually first manifests in young adulthood, and multiple sclerosis during midlife; however, each of these illnesses can occur at any PREPUBLICATION COPY—Uncorrected Proofs 

24 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE BOX 1-3 Sjögren’s Disease Highlights Features and Complexities Common in Autoimmune Disease • Most common in women • Can be diagnosed at different ages (Ramos-Casals et al., 2021) • May affect nearly any organ system • May involve systemic features and profound pain and fatigue • Associated with complications during pregnancy • Associated with increased risk of developing cancer (Vivino et al., 2019) • May lead to disability • Autoimmune response is complex and progresses over years • Commonly co-occurs with other autoimmune diseases age (Bar-Or, 2016; Cartee et al., 2016; Dall’Era et al., 2017; Lim et al., 2014; Somers et al., 2014). Availability of NIH Data on Research Spending for Autoimmune Disease The committee determined that NIH funding data would provide valuable information on the focus of NIH’s autoimmune disease research portfolio. The committee relied on two sources for that information: NIH’s Research, Condition, and Disease Categorization system (RCDC) and the NIH Research Portfolio Online Reporting Tools (RePORT) website.7 RCDC provides an overview of NIH funding, including a broad category for “autoimmune diseases” (referred to as “parent category”) and seven subcategories (referred to as “child categories”) of autoimmune diseases.8 These “child categories” provide added transparency to the public on funding for specific autoimmune diseases. The RePORT website provides public access to a variety of reporting tools, reports, data, and analyses of NIH research activities. One of the tools available on the RePORT website is the RePORTER module that allows users to search a repository of NIH- funded intramural and extramural research grants by RCDC spending 7 The NIH Reform Act of 2006 encouraged NIH to prioritize consistency and transparency in the reporting of its funded research. Implemented in 2008, the Research, Condition, and Disease Categorization (RCDC) system uses sophisticated text data mining (categorizing and clustering using words and multiword phrases) in conjunction with NIH-wide defini- tions used to match projects to specific funding categories (ERA, 2019; NIH, 2020). 8 The child categories of the parent category “autoimmune disease” are inflammatory bowel disease (includes Crohn’s disease), lupus, multiple sclerosis, rheumatoid arthritis, scleroderma, psoriasis, myasthenia gravis, and all other autoimmune disease research at NIH (McNamara, 2021). PREPUBLICATION COPY—Uncorrected Proofs 

INTRODUCTION 25 categories and to access publications and patents resulting from NIH funding. The committee analyzed data from fiscal year 2008 to 2020, the last year for which data were available at the time of analysis. To expedite data analysis, an external contractor with experience using NIH RePORT tools provided assistance in reviewing data on publications, clinical trials, and patents resulting directly from NIH autoimmune funded work. Appen- dix G describes the methods used to perform RePORTER analyses. To aid in assessing the 2008–2020 autoimmune disease research port- folio for the appearance of research topic patterns and trends, an external consultant used an artificial intelligence program to apply topic model- ing, a form of statistical modeling, to the data. Appendix H describes the methodology. The committee used PICO Portal, a publications manage- ment tool, to review sampled abstracts of funded research grants. The rationale and methods for sampling and for the committee’s review can be found in Chapter 6. The Study Process and Information Gathering The committee convened virtually ten times, and between these meet- ings, small groups of committee members participated in virtual meet- ings or conference calls to advance their work. The committee held three public sessions to gather information from individuals with expertise on topics and subjects of interest to the committee, including panels of repre- sentatives of NIH institutes, centers, and offices; experts on autoimmune diseases and autoimmune disease research from academia and disease- focused organizations; and individuals with autoimmune disease who provided insights into their lived experiences. The committee held public sessions during its first three meetings; Appendix C lists the agendas and presentation topics. In addition to information provided by invited speakers, at the instruc- tion of the committee, National Academies staff interviewed NIH repre- sentatives to gather information on approaches the NIH uses to advance collaboration on and coordination of autoimmune disease research, both in and outside NIH. The committee also obtained information from NIH via direct request to the relevant offices or ICs. These inquiries sought background and details on issues raised during presentations and com- mittee deliberations and on the NIH RePORT tools. All presentations and responses to information requests are available in the public access file for the project.9 Information on the missions, priorities, programs, 9 Available at https://www8.nationalacademies.org/pa/managerequest.aspx?key=HMD- BPH-20-11 (accessed April 15, 2022). PREPUBLICATION COPY—Uncorrected Proofs 

26 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE collaborations, and funding processes of NIH centers and institutes (ICs) came from a review of NIH websites supplemented with information presented by representatives of ICs and Offices of NIH at the committee’s public sessions. The committee, aided by National Academies staff, conducted litera- ture reviews to obtain information on the incidence and prevalence of autoimmune disease and other factors, such as associated comorbidities. The committee gave preference to U.S. data when it was appropriately rigorous and inclusive, but when U.S. data focused on small populations or lacked rigor, the committee used data from other countries in which health care systems and registries better enable the collection of data. Organization of the Report This report is organized into two parts and seven chapters. Part I: Intro- duction, Background on Autoimmune Diseases, Select Autoimmune Dis- eases, and Crosscutting Issues (Chapters 1–4) and Part II: NIH Autoimmune Disease Research Efforts and Analysis of Autoimmune Disease Research Funding (Chapters 5–7). In addition to this Introduction (Chapter 1), which provides an overview of the origin, purpose, and organization of the report, Chapter 2 (Background on Autoimmune Disease) provides information on how the autoimmune diseases are defined and an overview of the occur- rence and course of autoimmune diseases. Chapter 3 (Select Autoimmune Diseases) provides more information specific to the autoimmune diseases that the committee selected to focus on. The overview in Chapter 3 begins with a discussion of Sjögren’s disease because the disease illustrates many of the features and complexities common to autoimmune diseases, some of which are listed in Box 1-3. After Sjögren’s disease, Chapter 3 discusses other systemic autoimmune rheumatic diseases, followed by autoimmune diseases that affect a specific tissue or organ system, including skin, gas- trointestinal system, central nervous system, and endocrine system. Chapter 4 (Crosscutting Issues in Autoimmune Disease) discusses a number of issues that have implications for autoimmune disease research activities. Chapter 5 provides an overview of NIH autoimmune disease research efforts, and Chapter 6 provides an analysis of funding for the autoimmune diseases the committee focused on. Chapter 7 identifies opportunities for enhancing autoimmune disease research at NIH. REFERENCES AARDA (American Autoimmune Related Diseases Association), and NCAPG. 2011. The cost burden of autoimmune disease: The latest front in the war on healthcare spending. Eastpointe, MI: American Autoimmune Related Diseases Association Inc. PREPUBLICATION COPY—Uncorrected Proofs 

INTRODUCTION 27 ADCC (Autoimmune Diseases Coordinating Committee). 2005. Progress in autoimmune dis- eases research. Bethesda, MD: National Institutes of Health: Autoimmune Diseases Coordinating Committee. Amaro, F., and F. Chiarelli. 2020. Growth and puberty in children with inflammatory bowel diseases. Biomedicines 8(11). Arbuckle, M. R., M. T. McClain, M. V. Rubertone, R. H. Scofield, G. J. Dennis, J. A. James, and J. B. Harley. 2003. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. The New England Journal of Medicine 349(16):1526–1533. Autoimmune Association. 2021a. About us. https://autoimmune.org/about-us (accessed November 29, 2021). Autoimmune Association. 2021b. Autoimmune disease list. https://autoimmune.org/about- us (accessed November 29, 2021). Autoimmune Registry, Inc. 2020. The autoimmune diseases. https://www.autoimmuneregistry. org/autoimmune-diseases (accessed April 12, 2021). Autoimmune Registry, Inc. 2021. About Autoimmune Registry, Inc. https://www.autoimmu- neregistry.org/about-us (accessed June 22, 2021). Bar-Or, A. 2016. Multiple sclerosis and related disorders: Evolving pathophysiologic in- sights. The Lancet Neurology 15(1):9–11. Calabrese, M., D. Marastoni, F. Crescenzo, and A. Scalfari. 2021. Early multiple sclerosis: Diagnostic challenges in clinically and radiologically isolated syndrome patients. Cur- rent Opinion in Neurology 34(3):277–285. Cartee, A. K., L. A. Owens, B. D. Lahr, B. P. Yawn, J. A. Murray, and Y. C. Kudva. 2016. Incidence of type 1 diabetes is not increasing in a population-based cohort in Olmsted County, Minnesota, USA. Mayo Clinic Proceedings 91(8):1066–1073. Cirillo, F., P. Lazzeroni, C. Sartori, and M. E. Street. 2017. Inflammatory diseases and growth: Effects on the GH-IGF axis and on growth plate. International Journal of Molecular Sci- ences 18(9), 1878. https://doi.org/10.3390/ijms18091878. Cojocaru, M., I. M. Cojocaru, and I. Silosi. 2010. Multiple autoimmune syndrome. Maedica (Bucur) 5(2):132–134. Dall’Era, M. 2013. Systemic lupus erythematosus. In Current diagnosis & treatment: Rheumatol- ogy, 3rd ed., edited by J. B. Imboden, D. B. Hellmann, and J. H. Stone. New York, NY: McGraw-Hill. Dall’Era, M., M. G. Cisternas, K. Snipes, L. J. Herrinton, C. Gordon, and C. G. Helmick. 2017. The incidence and prevalence of systemic lupus erythematosus in San Francisco County, California: The California Lupus Surveillance Project. Arthritis & Rheumatology 69(10):1996–2005. Dinse, G. E., C. G. Parks, C. R. Weinberg, C. A. Co, J. Wilkerson, D. C. Zeldin, E. K. L. Chan, and F. W. Miller. 2020. Increasing prevalence of antinuclear antibodies in the United States. Arthritis & Rheumatology 72(6):1026–1035. ERA (Electronic Research Assocation). 2019. Overview of RCDC. https://era.nih.gov/about- era/nih-and-grantor/other/rcdc.htm (accessed November 3, 2021). Franks, A. L., and J. E. Slansky. 2012. Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. Anticancer Research 32(4):1119–1136. Fridkis-Hareli, M. 2008. Immunogenetic mechanisms for the coexistence of organ-specific and systemic autoimmune diseases. Journal of Autoimmune Diseases 5:1. Groot, N., D. Shaikhani, Y. K. O. Teng, K. de Leeuw, M. Bijl, R. J. E. M. Dolhain, E. Zirkzee, R. Fritsch-Stork, I. E. M. Bultink, and S. Kamphuis. 2019. Long-term clinical outcomes in a cohort of adults with childhood-onset systemic lupus erythematosus. Arthritis & Rheumatology 71(2):290–301. PREPUBLICATION COPY—Uncorrected Proofs 

28 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE Heshin-Bekenstein, M., L. Perl, A. O. Hersh, E. von Scheven, E. Yelin, L. Trupin, J. Yazdany, and E. F. Lawson. 2018. Final adult height of patients with childhood-onset systemic lupus erythematosus: A cross sectional analysis. Pediatric Rheumatology Online Journal 16(1):30. HHS (Department of Health and Human Services). 2022. HHS agencies & offices. https:// www.hhs.gov/about/agencies/hhs-agencies-and-offices/index.html (accessed Janu- ary 14, 2022). IOM (Institute of Medicine). 2010. Women’s health research: Progress, pitfalls, and promise. Washington, DC: The National Academies Press. Lim, L. S. H., A. Lefebvre, S. Benseler, and E. D. Silverman. 2013. Longterm outcomes and damage accrual in patients with childhood systemic lupus erythematosus with psycho- sis and severe cognitive dysfunction. Journal of Rheumatology 40(4):513–519. Lim, L. S. H., E. Pullenayegum, L. Lim, D. Gladman, B. Feldman, and E. Silverman. 2017. From childhood to adulthood: The trajectory of damage in patients with juvenile-onset systemic lupus erythematosus. Arthritis Care & Research 69(11):1627–1635. Lim, S. S., A. R. Bayakly, C. G. Helmick, C. Gordon, K. A. Easley, and C. Drenkard. 2014. The incidence and prevalence of systemic lupus erythematosus, 2002–2004: The Geor- gia Lupus Registry. Arthritis & Rheumatology 66(2):357–368. https://doi.org/10.1002/ art.38239. Mauras, N., B. Buckingham, N. H. White, E. Tsalikian, S. A. Weinzimer, B. Jo, A. Cato, L. A. Fox, T. Aye, A. M. Arbelaez, T. Hershey, M. Tansey, W. Tamborlane, L. C. Foland- Ross, H. Shen, K. Englert, P. Mazaika, M. Marzelli, and A. L. Reiss, for the Diabetes Research in Children Network (DirecNet). 2021. Impact of type 1 diabetes in the de- veloping brain in children: A longitudinal study. Diabetes Care 44(4):983–992. https:// doi.org/10.2337/dc20-2125. Mayer-Davis, E. J., D. Dabelea, and J. M. Lawrence. 2017. Incidence trends of type 1 and type 2 diabetes among youths, 2002–2012. The New England Journal of Medicine 376(15):1419–1429. McNamara, J. 2021. Autoimmune disease research supported by extramural NIAID. Paper read at NASEM Committee for the Assessment of NIH Research on Autoimmune Diseases: Meeting 2 (Continuation), February 1, 2021, Webinar. Mifflin, K. A., and B. J. Kerr. 2017. Pain in autoimmune disorders. Journal of Neuroscience Research 95(6):1282–1294. Mitchell, D. M. 2017. Growth in patients with type 1 diabetes. Current Opinion in Endocrinol- ogy, Diabetes, and Obesity 24(1):67–72. NIAID (National Institute of Allergy and Infectious Diseases). 2017. NIAID strategic plan 2017. Bethesda, MD: National Institute of Allergy and Infectious Diseases. NIAID. 2021. NIH autoimmune diseases coordinating committee. https://www.niaid.nih.gov/ about/autoimmune-diseases-committee (accessed November 29, 2021). NIEHS (National Institute of Environmental Health Sciences). 2021. Autoimmune diseases. https://www.niehs.nih.gov/health/topics/conditions/autoimmune/index.cfm (ac- cessed April 28, 2021). NIH (National Institues of Health). 2017. Mission and goals. https://www.nih.gov/about- nih/what-we-do/mission-goals (accessed October 27, 2021). NIH. 2020. Estimates of funding for various research, condition, and disease categories (RCDC). https://report.nih.gov/funding/categorical-spending#/ (accessed April 12, 2021). NIH. 2021. Actual total obligations by institute and center: FY 2000–FY 2020. Bethesda, MD: Na- tional Institutes of Health. https://officeofbudget.od.nih.gov/pdfs/FY21/spending- hist/Actual%20Obligations%20By%20IC%20FY%202000%20-%20FY%202020%20(V). pdf (accessed September 2, 2021). PREPUBLICATION COPY—Uncorrected Proofs 

INTRODUCTION 29 Ramos-Casals, M., N. Acar-Denizli, A. Vissink, P. Brito-Zerón, X. Li, F. Carubbi, R. Priori, N. Toplak, C. Baldini, E. Faugier-Fuentes, A. A. Kruize, T. Mandl, M. Tomiita, S. Gandolfo, K. Hashimoto, G. Hernandez-Molina, B. Hofauer, S. Mendieta-Zerón, A. Rasmussen, P. Sandhya, D. Sene, V. F. M. Trevisani, D. Isenberg, E. Sundberg, S. G. Pasoto, A. Sebastian, Y. Suzuki, S. Retamozo, B. Xu, R. Giacomelli, A. Gattamelata, M. Bizjak, S. Bombardieri, R.-E. Loor-Chavez, A. Hinrichs, P. Olsson, H. Bootsma, S. M. Lieberman, and the Sjögren Big Data Consortium. 2021. Childhood-onset of primary Sjögren’s syn- drome: Phenotypic characterization at diagnosis of 158 children. Rheumatology (Oxford) 60(10):4558–4567. Reno, C. M., A. Skinner, J. Bayles, Y. S. Chen, D. Daphna-Iken, and S. J. Fisher. 2018. Severe hypoglycemia-induced sudden death is mediated by both cardiac arrhythmias and seizures. American Journal of Physiology: Endocrinology and Metabolism 315(2):E240–E249. https://doi.org/10.1152/ajpendo.00442.2017. Rojas-Villarraga, A., J. Amaya-Amaya, A. Rodriguez-Rodriguez, R. D. Mantilla, and J. M. Anaya. 2012. Introducing polyautoimmunity: Secondary autoimmune diseases no lon- ger exist. Autoimmune Diseases 2012:254319. Ruano, L., M. Branco, E. Portaccio, B. Goretti, C. Niccolai, F. Patti, C. Chisari, P. Gallo, P. Grossi, A. Ghezzi, M. Roscio, F. Mattioli, C. Stampatori, M. Simone, R. G. Viterbo, and M. P. Amato. 2018. Patients with paediatric-onset multiple sclerosis are at higher risk of cognitive impairment in adulthood: An italian collaborative study. Multiple Sclerosis 24(9):1234–1242. Shivashankar, R., W. J. Tremaine, W. S. Harmsen, and E. V. Loftus, Jr. 2017. Incidence and prevalence of Crohn’s disease and ulcerative colitis in Olmsted County, Minnesota from 1970 through 2010. Clinical Gastroenterology and Hepatology 15(6):857–863. Somers, E. C., W. Marder, P. Cagnoli, E. E. Lewis, P. DeGuire, C. Gordon, C. G. Helmick, L. Wang, J. J. Wing, J. P. Dhar, J. Leisen, D. Shaltis, and W. J. McCune. 2014. Population- based incidence and prevalence of systemic lupus erythematosus: The Michigan Lupus Epidemiology and Surveillance program. Arthritis & Rheumatology 66(2):369–378. https://doi.org/10.1002/art.38238. Thomas, S. L., C. Griffiths, L. Smeeth, C. Rooney, and A. J. Hall. 2010. Burden of mortality associated with autoimmune diseases among females in the United Kingdom. American Journal of Public Health 100(11):2279–2287. United States Census Bureau. 2021. Historical population change data (1910–2020). https:// www.census.gov/data/tables/time-series/dec/popchange-data-text.html (accessed November 2, 2021). Vivino, F. B., V. Y. Bunya, G. Massaro-Giordano, C. R. Johr, S. L. Giattino, A. Schorpion, B. Shafer, A. Peck, K. Sivils, A. Rasmussen, J. A. Chiorini, J. He, and J. L. Ambrus, Jr. 2019. Sjögren’s syndrome: An update on disease pathogenesis, clinical manifestations and treatment. Clinical Immunology 203:81–121. Walsh, S. J., and L. M. Rau. 2000. Autoimmune diseases: A leading cause of death among young and middle-aged women in the United States. American Journal of Public Health 90(9):1463–1466. Williams, J. W., L. H. Huang, and G. J. Randolph. 2019. Cytokine circuits in cardiovascular disease. Immunity 50(4):941–954. Yen, E. Y., and R. R. Singh. 2018. Brief report: Lupus-an unrecognized leading cause of death in young females: A population-based study using nationwide death certificates, 2000– 2015. Arthritis & Rheumatology 70(8):1251–1255. https://doi.org/10.1002/art.40512. PREPUBLICATION COPY—Uncorrected Proofs 

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