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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 diseases, 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 (Cojocaru 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 complications. Autoimmune diseases are chronic and lifelong and can cause significant 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, 2017; Mauras et al., 2021; Mitchell, 2017; Ruano et al., 2018). Autoimmune disease can also be fatal; uncontrolled type 1 diabetes is well-known to be life-threatening (Reno et al., 2018), a 2018 study determined systemic lupus erythematosus to be a leading cause of

death in young females in the United States (Yen and Singh, 2018), and autoimmune diseases as a group rank among the 10 leading causes of death for females (Thomas et al., 2010; Walsh and Rau, 2000). There are no known cures for autoimmune diseases.

There are 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 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 societal costs of autoimmune diseases are substantial but difficult to estimate overall, because 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 disability” (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. Autoimmune disease research activities occur across the ICs through both extramural and intramural research activities. In fiscal year 2020, NIH’s budget obligations³ were approximately $41.5 billion, of which NIH spent $1.1

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¹ NIH established the ADCC in 1998 in response to congressional encouragement to facilitate coordination of autoimmune disease research across NIH, federal agencies, professional societies, and patient and advocacy organizations (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 Services (CMS), Food and Drug Administration (FDA), Health Resources and Services Administration (HRSA), Indian Health Service (IHS), and Substance Abuse and Mental Health Services Administration (SAMHSA).

³ Actual total obligations.

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 Medicine (National Academies) to identify and review NIH’s research efforts in this broad area. In response, the National Academies convened the Committee for the Assessment of NIH Research on Autoimmune Diseases (the committee) to respond to this request. The 13-member interdisciplinary committee consisted of experts in autoimmune diseases, immunology, epidemiology, environmental health, neurology, nephrology, gastroenterology, 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 autoimmune 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 particular 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 barriers 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 autoimmune disease research funding focused on a select number of autoimmune

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⁴ Further Consolidated Appropriations Act, H.R.1865, 116th Cong., 1st sess., Congressional Record 165, no. 204, daily ed. (December 17, 2019): H11071.

conditions over a select period of time. The committee notes that there is neither a consensus definition of autoimmune disease, nor 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 Autoimmune Association (formerly named American Autoimmune Related

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⁵ The Autoimmune Registry, Inc., is a nonprofit organization that serves as a hub for research, statistics, and patient data on all autoimmune disease (Autoimmune Registry Inc., 2021).

Diseases Association, or AARDA)⁶ compiled two longer lists of autoimmune diseases that include 147 and 150 diseases, respectively (Autoimmune Association, 2021b; Autoimmune Registry Inc., 2020). Appendix B lists the diseases the Autoimmune Association identifies as autoimmune 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 having “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 autoimmune diseases. Box 1-2 lists these factors, and Table 1-1 lists the diseases 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.

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⁶ The Autoimmune Association (previously known as the American Association of Autoimmune Related Disorders [AARDA]) is a nonprofit organization focused on the eradication of autoimmune diseases and impact of autoimmunity (Autoimmune Association, 2021a).

TABLE 1-1 Disease Selection Considerations

^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.

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 arthritis, 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: Progress, 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, antiphospholipid syndrome, primary biliary cholangitis, and autoimmune thyroid disease, each of which also affects more women than men. The committee 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 progression of disease and outcomes.

Diseases That May Encompass Multiple Systems and Comorbidities.

Unlike many other illnesses, autoimmune diseases affect multiple organ systems (e.g., skin, kidney, lung, joints, and brain), sometimes 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 accompany rheumatoid arthritis, systemic lupus erythematous, and related illnesses. 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 spectrum 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 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

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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 RCDC system uses sophisticated text data mining (categorizing and clustering using words and multiword phrases) in conjunction with NIH-wide definitions 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).

NIH-funded intramural and extramural research grants by RCDC spending 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. Appendix G describes the methods used to perform RePORTER analyses.

To aid in assessing the 2008–2020 autoimmune disease research portfolio for the appearance of research topic patterns and trends, an external consultant used an artificial intelligence program to apply topic modeling, a form of statistical modeling, to the data. Appendix H describes the methodology. The committee used PICO Portal, a publications management 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 10 times, and between these meetings, small groups of committee members participated in virtual meetings 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 representatives of NIH ICs 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 instruction of the committee, National Academies staff interviewed NIH representatives to gather information on approaches 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 committee 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,

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⁹ Available at https://www8.nationalacademies.org/pa/managerequest.aspx?key=HMD-BPH-20-11 (accessed April 15, 2022).

collaborations, and funding processes of NIH 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 literature 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 they were 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: Introduction, Background on Autoimmune Diseases, Select Autoimmune Diseases, 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 occurrence 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, gastrointestinal 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.

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