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Enhancing NIH Research on Autoimmune Disease (2022)

Chapter:7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health

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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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Suggested Citation:"7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health." National Academies of Sciences, Engineering, and Medicine. 2022. Enhancing NIH Research on Autoimmune Disease. Washington, DC: The National Academies Press. doi: 10.17226/26554.
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7 Opportunities and Options for Enhancing Autoimmune Disease Research at the National Institutes of Health In this chapter the committee reviews its response to the statement of task and highlights observations that form the basis for its consideration of potential opportunities and options for enhancing autoimmune disease research at NIH. Chapters 2 and 3 provide ample evidence that autoimmune diseases exact a difficult toll and inflict severe burdens on the U.S. population, with consequences that compromise quality of life for those afflicted. Many autoimmune diseases affect women predominantly, and the incidence and prevalence of these diseases appears to be rising in certain groups, such as children and adolescents in the case of two of the most common autoimmune diseases, namely inflammatory bowel disease and type 1 diabetes. The burden of some autoimmune diseases is higher among spe- cific minority racial and ethnic populations, which also contributes to the importance of enhancing research in these areas. As described in Chapter 2, the committee realized that it faced a daunting task given definitional issues and the lack of basic data. It found that autoimmunity and autoimmune disease are evolving and dynamic areas in which definitions of autoimmune disease and the number of diseases identified as such continue to evolve and change. Recent scien- tific advances have blurred the definition of autoimmune disease, there is no consensus on the best terms or methods to conceptualize autoim- mune disease to meet the differing views and purposes of basic and clinical research, and there is no consensus regarding the number of 411 PREPUBLICATION COPY—Uncorrected Proofs

412 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE autoimmune diseases. The committee could not identify a concerted NIH effort addressing these issues. A second challenge the committee faced was the lack of basic epide- miologic data on the incidence and prevalence of autoimmune diseases. There is no mandatory reporting system or national registry for autoim- mune diseases in the United States. Existing incidence and prevalence data often come from other countries that have health care systems cover- ing the entire population. In the United States, data are incomplete and often outdated, which can limit the ability to assess if progress has been or is being made in reducing the burden of these diseases. The committee could not identify a concerted NIH effort to improve the availability of population-level data on autoimmune disease. The committee’s examination of 11 diseases illustrating the spectrum of autoimmune diseases emphasizes the variation in what is known and unknown about each disease. For example, gaps exist in the epidemiology of most autoimmune diseases; basic molecular mechanisms are not clearly elucidated for many autoimmune diseases; important questions remain regarding risk factors and etiology for most autoimmune diseases; and diagnostic tools are limited or lacking for some autoimmune diseases. Further, there is tremendous variation in how diseases present, progress, and evolve, which complicates diagnosis and treatment. Autoimmune diseases can be treated; treatment is aimed at reducing symptoms and improving function and quality of life, but for some autoimmune dis- eases, information is lacking on how best to target therapies to individu- als. Finally, the committee found limited information on the social and economic impact of autoimmune diseases on affected individuals and their families. Chapter 4 describes commonalities among autoimmune diseases. These commonalities suggest common immune pathways among some diseases or groups of diseases, including the role of genetics, biologic sex, and environmental exposures. Advances in technology allow researchers to capture, manipulate, and optimize enormous quantities of data from basic and clinical research, which they can in turn use to form hypoth- eses. The committee believes these commonalities regarding shared gene and immune pathways may provide additional and significant insights that can further the development of treatments and therapies that could benefit patients suffering with these diseases. For this area of inquiry to advance, a multidisciplinary approach will be needed that draws upon the expertise of researchers from across the NIH. Chapter 5 describes the NIH research grant process and coordination of autoimmune disease research. The committee found that the Autoim- mune Disease Coordinating Committee (ADCC) has no dedicated fund- ing or staff and functions as a convener of Institutes and Centers (ICs) PREPUBLICATION COPY—Uncorrected Proofs

ENHANCING AUTOIMMUNE DISEASE RESEARCH 413 and external partners. It was unable to assess the extent to which ADCC activities have expanded, renewed the focus on, or provided enhanced coordination of autoimmune disease research. The committee reviewed the NIH research portfolio on autoimmune disease with an appreciation of the research gaps highlighted in chapters 2 through 4. The general framework for this review included, to the extent possible, reviewing a set of inputs, activities, and outputs. Among the inputs reviewed were NIH spending for autoimmune disease research grants and procedures for awarding grants, as well a review of individual IC missions and strategic plans. The committee found that there is no central repository for information on autoimmune disease research activ- ity undertaken by ICs across the NIH. Committee members reviewed IC strategic plans, websites, and other information to obtain insights into the autoimmune research priorities of the ICs reviewed and to identify which autoimmune diseases might be relevant to their missions. The committee notes that the lack of a central repository for autoimmune disease research at the NIH hampers the ability of individuals in and outside of NIH, and in and outside of the research enterprise, to readily access this information and consequently limits transparency and communication with the public and other stakeholders. The committee found that NIH spending on autoimmune disease research has remained constant at about 2.8 percent of total spending between 2008 and 2020 while there are indications that some autoimmune diseases are on the rise and that many individuals are living with autoim- mune disease. If resources increase for autoimmune disease research, a strategy for prioritizing, leveraging, and assuring that funds are invested in the areas of highest scientific priority would be essential. Similarly, if budgets remain constrained, the need for strategic prioritization is even greater. The committee did not find evidence of current crosscutting auto- immune disease research budgeting, planning or prioritization. The committee next reviewed the focus of the funded autoimmune disease research grants as the statement of task requested. It used three different approaches which indicated significant variation in the focus of research grants. This is consistent with the fact that 73 percent of autoim- mune disease research grants are investigator initiated. The committee notes that in the NIH RCDC analysis of co-occurring RCDC spending categories, autoimmune disease relevant themes such as minority health, pain research, and co-occurring complications, conditions, or diseases (e.g. chronic pain, cancer, cardiovascular, depression, eye disease and dis- orders) co-occurred in less than 10 percent of autoimmune disease grants. Spending category themes related to burden of illness, caregiving, and health services co-occurred in less than 2 percent of grants. PREPUBLICATION COPY—Uncorrected Proofs

414 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE The analysis of the focus of autoimmune disease grants using differ- ent methods provided limited information. The committee had no basis upon which to determine whether: 1) the funded grants represents the most promising, innovative, or impactful autoimmune disease research areas; 2) dollars are appropriately distributed by research topic area (e.g. crosscutting research, basic science, clinical science, specific autoimmune diseases); and 3) fellowships, research career and training program grants appropriately support the development of a multidisciplinary and diverse autoimmune research workforce. A crosscutting strategic plan to guide current research activities with details on specific goals, objectives, time- lines and milestones would have provided an important reference point to guide the assessment of the current portfolio. Developed 20 years ago, the last autoimmune disease research plan lacked such details. Shared immune pathways among autoimmune diseases noted ear- lier suggest opportunities for cross-IC collaboration and coordination of research activities. The committee’s analysis of IC collaborations on joint research funding opportunities from 2008–2020 indicates an average of four or fewer IC collaborations during the period. Based on this find- ing, the committee raises the question as to whether ICs can do more to collaboratively leverage cross-NIH expertise and resources to advance autoimmune disease research activities. Finally, the committee attempted to assess the output or accomplish- ments associated with funded research on autoimmune disease. This effort included a high-level examination of clinical trial activity represent- ing the translation of research knowledge into interventions that influ- ence health-related biomedical or behavioral outcomes. Clinical trials have centered on certain autoimmune diseases but not for other diseases that receive limited funding, perhaps indicating that research has not yet progressed to this stage. The committee also considered a number of bib- liometric indicators: number of publications; the relative citation ratio, a research influence indicator; and the journal impact factor which indicates the quality of the journal that published the article. A final task involved identification of the number of patents associated with autoimmune dis- ease research grants as an indicator of innovation and the translational value of autoimmune disease research activities. The committee’s review of the NIH autoimmune disease research portfolio confirms that much extraordinary work related to autoimmune disease has been undertaken and likely will continue. The committee was struck by the number of research grants (8,470) it identified as related to autoimmune disease during the fiscal year 2008–2020 period and the extent to which knowledge associated with these grants has been dissemi- nated to the research community through publications, translated into PREPUBLICATION COPY—Uncorrected Proofs

ENHANCING AUTOIMMUNE DISEASE RESEARCH 415 potential interventions, and driven innovation as indicated by approved patents. In sum, the committee found that autoimmune diseases impact the lives of millions of Americans. Autoimmune diseases are complex and share commonalities that would benefit from a coordinated, multidisci- plinary research approach to better understand basic mechanisms, etiol- ogy, risk factors, and to support the development of interventions to miti- gate the impact of autoimmune diseases and associated co-morbidities and complications across the lifespan. Current NIH autoimmune disease research efforts are guided by a dated research plan and efforts to coor- dinate autoimmune disease research are minimal. Information on auto- immune disease research activities is difficult to identify across ICs and this hinders transparency and communication with internal and external stakeholders. Finally, the committee found there is no central entity with capabilities to improve communication, management, priority setting, and accountability for autoimmune disease research. The committee con- cludes that these findings can be usefully framed as future opportunities for enhancing the research enterprise for autoimmune diseases. PLANNING, COLLABORATION, AND INNOVATION The committee offers a framework of five essential elements to enhance the rapid advancement and improvement in autoimmune disease research—(1) strategic research planning to set priorities, (2) an emphasis on coordinating across NIH ICs and enhancing collaborative research given the crosscutting nature of autoimmune diseases, (3) an orientation toward innovation, (4) a focus on evaluating the autoimmune research portfolio to determine progress made across NIH, and (5) resources to support planning, collaboration, and innovation. These critical elements, which can be viewed as complementary, are recognized by research lit- erature, NIH in its overall strategic plan, and the findings of this study. While the committee recognizes that the diffuse and investigator-initiated nature of NIH research, and of autoimmune disease research in particular, has many well-described and accepted advantages, this approach does not optimally promote these five elements given barriers identified by the committee. While several individual ICs address autoimmune diseases in strategic plans and may reference elements such as collaboration and evaluation, others do not. Beyond individual ICs, an overarching barrier is the absence of an overall strategic research plan for NIH work on autoimmune disease that would prioritize coordination of and collaboration in research, act as an impetus to increased innovation, and include attention to evaluation. The NIH ADCC has not developed a strategic research plan in this area PREPUBLICATION COPY—Uncorrected Proofs

416 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE since 2002, and this plan did not have an evaluative component given the absence of milestones or metrics. In contrast, the National Plan to Address Alzheimer’s Disease, another area of crosscutting attention by various ICs, lays out guiding principles, concrete goals as building blocks for transfor- mation which reference the importance of tracking progress, and related strategies that identify lead agencies and potential research partners in the public and private sectors (AIM, 2021; HHS, 2020). In the area of autoimmune disease research, a relatively indepen- dent, structured, and ongoing examination of the research conducted can identify where gaps and opportunities lie. This analysis can then inform planning for how to address those gaps and opportunities most success- fully, an effort that would also benefit from a detailed but not prescriptive strategic plan. Currently, neither a rigorous evaluation nor planning for autoimmune disease research across NIH occurs in an overarching, sus- tained, and resourced fashion. While the ADCC was tasked to coordinate autoimmune disease research, the committee determined that it currently functions primarily as a convener of ICs and external partners. While meeting participants share information and may coordinate their activities on autoimmune disease research, the ADCC does not have central responsibility and accountability for driving activities and does not have the funding to spur targeted research by ICs. During the course of this review, the committee identified an opportu- nity not just for filling gaps that may fall between the work of diverse ICs, but as discussed in Chapter 4, capturing and leveraging an understand- ing of the crosscutting nature of autoimmune diseases, including their underlying common disease mechanisms, risk factors, and commonalities such as coexisting illnesses. The committee believes that emerging and evolving science now makes those connections more achievable than ever before. Such information would doubtless serve as building blocks for and would accelerate innovative progress toward prevention, treatment, and cure. Some of this work can advance without the infusion of major new resources. However the committee believes that any centralized entity, to be effective, will require new resources; and that a broader and bet- ter research enterprise on autoimmune disease has a greater potential to bring relief to patients and their families. The committee considered five options for enhancing autoimmune disease research and resulting outcomes: increased funding, two options for coordinating research, establishing a national strategic plan, establish- ing a new institute, and creating a special office for autoimmune disease research. The committee recognizes that no one option will transform the autoimmune disease research enterprise, and that each option involves PREPUBLICATION COPY—Uncorrected Proofs

ENHANCING AUTOIMMUNE DISEASE RESEARCH 417 tradeoffs. Table 7-1 provides the committee’s description of each option, noting advantages and disadvantages for each and offering a high-level assessment of cost and political feasibility. As discussed below, the com- mittee found that the best option for addressing these challenges and opportunities would be creating an office of autoimmune disease in the Office of the NIH Director (OD) that is funded appropriately. Such an office would be positioned to respond to the committee’s concerns by: • Facilitating cross-NIH multidisciplinary collaboration and stimu- lating innovation around autoimmune disease research; • Engaging in priority setting, strategic planning, and implemen- tation; • Budgeting for and allocating available research funds in align- ment with the strategic plan; • Managing and evaluating research efforts; • Communicating with key stakeholders; and • Providing visible leadership on autoimmune disease research. Option 1: Increased Funding for Autoimmune Disease Research Given the flat line of research spending levels over the past 12 years, the committee believes that increased funding will be an indispensable component of any effort to enhance autoimmune disease research oppor- tunities, and thus it lists that option first. Options for use of increased funding include directing funding to certain ICs, such as those whose mission is more directly related to autoimmune disease issues of con- cern (e.g., National Institute of Diabetes and Digestive and Kidney Dis- eases , National Institute of Allergy and Infectious Diseases, and National Institute of Arthritis and Musculoskeletal and Skin Diseases) or increas- ing funding to ICs which are highly relevant but less well funded (e.g., National Institute of Environmental Health Sciences). ICs with smaller total budgets would have more funding to drive and solicit specific research on autoimmune disease and to bring more dollars and expertise to the table to collaborate meaningfully. As a result, more and potentially better collaborations might occur. The design of increased funding can include such options as a com- mon fund or direction to certain focused activities. Funding for an “auto- immune disease research common fund” could specifically support more crosscutting research activities that could foster collaboration among ICs. More “risky” or expensive but high-payoff research collaborations could be undertaken. One approach would be to model such a fund after the NIH Common Fund, which makes funds available to address high-priority emerging scientific opportunities and pressing challenges in biomedical PREPUBLICATION COPY—Uncorrected Proofs

418 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE TABLE 7-1  Options for Enhancing NIH Autoimmune Disease Research Option 1. Increased Funding for Autoimmune Disease Research • Increased funding to certain ICs Funding may • Increased funding for crosscutting activities (autoimmune disease include: research common fund) • Increased funding for certain focused activities • Opportunity for accelerated discovery. • Specific ICs, particularly those that are highly relevant but less well-funded, would have more funding to solicit specific research on autoimmune disease and to “bring dollars and expertise to the table” to collaborate meaningfully. Thus more and better collabora- Pros: Potential tions might occur. Benefits and • More “risky” or expensive but high-payoff research collaborations Advantages could be undertaken. • Increased funding for specific topics of research or workforce development. • Relatively low administrative burden since it would leverage mechanisms already in place. • Funding increases are uncertain/unpredictable making planning difficult. • Unhelpful competition for limited new resources among ICs—and among autoimmune diseases research areas. Cons: Potential • Without major new funding, new investments in one area may be Concerns and offset by cuts in another. Disadvantages • There may be opposition to earmarking funding for autoimmune disease research. • Funding may not address issues of coordination, prioritization, or workforce development. Costs • Variable but could be high Feasibility • Contingent on internal NIH and external advocacy and substantial congressional support. Option 2. Enhanced Coordination Options 2a. Revitalize ADCC Pros: Potential • Would not require creation of a new entity Benefits and • Possibility of drawing on past experience with 2002 Autoimmune Advantages Disease Strategic Research Plan in developing a new strategic plan. • Lacks IC neutrality by virtue of its placement within NIAID. • ADCC lacks resources to support ICs for credible implementation Cons: Potential of strategic plan. Concerns and • Potential reluctance to significantly resource and empower an of- Disadvantages fice that has not had a significant leadership role. • ADCC cannot hold ICs accountable for implementing or funding research according to the strategic plan. PREPUBLICATION COPY—Uncorrected Proofs

ENHANCING AUTOIMMUNE DISEASE RESEARCH 419 TABLE 7-1 Continued Costs • Low Feasibility • Easy but would require additional funding to support strategic plan development. 2b. Establish an Health and Human Services (HHS) Autoimmune Disease Coordinat- ing Committee • Would raise the visibility of autoimmune diseases to the cabinet level. • Engages and potentially leverages other HHS agencies, including their expertise, resources, and reach. Pros: Potential • Could anticipate and inform issues—such as special populations Benefits and (racial and ethnic minority populations, women), payment for Advantages health care services; regulation of drugs and devices; and public health issues. • Could enhance engagement with non-HHS agencies, e.g., Social Security Administration regarding disability determinations. • Greater accountability. • Downside of broad engagement can be greater bureaucracy (in- Cons: Potential cluding neglect, and/or resistance); high-level products with little Concerns and depth; slowness; lack of external support and politicization. Disadvantages • Would require creation of the body and need appropriate resources (staff, funding, authority). Costs • Moderate Feasibility • Moderate difficulty: some resistance may be inevitable. Option 3: Congressionally Mandated National Autoimmune Disease and Autoimmu- nity Plan Pros: Potential • Imprimatur of Congress brings weight, attention, expectation of Benefits and results, and likely resources to the issue. Advantages • Delineated activities and deliverables provide specificity and focus. • Focus on a single disease may obscure or inadvertently exclude Cons: Potential other conditions. Concerns and • Absent specificity, accountability for results may be unclear or dif- Disadvantages fuse. Costs • Moderate Feasibility • Would require Congressional action. continued PREPUBLICATION COPY—Uncorrected Proofs

420 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE TABLE 7-1 Continued Option 4: Create a New National Institute of Autoimmune Disease and Autoimmu- nity • Significantly elevates visibility and status of autoimmune disease research within NIH and externally through leadership, infrastruc- ture, and funding. • Provides sustained leadership and focus to autoimmune disease research. IC Director, staff, and their external advisers are thinking Pros: Potential and working full time on solving autoimmune disease challenges Benefits and through extramural, intramural, training, communication, and Advantages outreach activities. • De facto coordinating body that is crosscutting rather than autoim- mune disease-specific. • Establishes clear focal point within NIH and externally. Internal and external accountability and transparency for autoimmune disease research may improve. • Would require time to conduct review and receive internal and external input on the creation of a new Institute. • Substantial costs to administratively create and sustain; new appro- Cons: Potential priations would be needed to avoid reducing autoimmune disease Concerns and activities in other ICs. Disadvantages • Potential resistance from other institutes. • A weak, underfunded Institute can give the illusion of increased effort and thus can be worse than an admittedly diffused effort in well-established but less focused ICs. Costs • High Feasibility • Substantial political obstacles can attend the creation of a new institute. • Would require congressional approval. Option 5: Create an Office of Autoimmune Disease/Autoimmunity Research within the Office of the NIH Director Realistically, the impact of such an Office will likely be proportionate to the extent to which it has and controls resources. Thus two options for an Office are described. • Elevates visibility, provides sustained leadership, and establishes a clear focal point for autoimmune disease research within NIH and externally through extramural, intramural, training, communica- tion and outreach activities. • De facto coordinating body that is crosscutting rather than autoim- Pros: Potential mune disease specific. Benefits and • Internal and external accountability and transparency for autoim- Advantages mune disease research may improve. • May provide, though to a lesser extent, many of the benefits of a new IC enumerated in Option 4, with fewer bureaucratic and other costs or controversies. • Establishes direct linkage and interactions with NIH Director and other NIH OD offices. PREPUBLICATION COPY—Uncorrected Proofs

ENHANCING AUTOIMMUNE DISEASE RESEARCH 421 TABLE 7-1 Continued • Would require administrative resources in staffing and infrastruc- Cons: Potential ture to conduct strategic planning, cross-IC and cross-governmen- Concerns and tal collaboration, external communication and dissemination, and Disadvantages stakeholder engagement. Feasibility • More feasible than the creation of an Institute. Option 5a. Create an Office with substantial control over NIH autoimmune disease research and resources • Would have funding to stimulate new crosscutting and collabora- Pros: Potential tive autoimmune disease research and enhance workforce develop- Benefits and ment. Advantages • Would have accountability for funded research activities. Costs • Moderate to High (in comparison to Option 5b) Option 5b: Create an Office without substantial control of NIH autoimmune disease research resources Cons: Potential • The Office would be accountable for its own activities but less so Concerns and for those controlling resources in other ICs. Disadvantages Costs • Moderate research that no single NIH IC can address on its own. Other options would be to model focused autoimmune research activities after other trans-NIH activities such as the All of Us Research Program1, an effort that seeks to advance individualized health care by enrolling one million or more participants to contribute their health data over many years, or the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, an effort that seeks to advance the understanding of the brain though development and application of breakthrough neuro- technologies.2 Such initiatives, however, are generally time-limited and are often focused or limited in topic or scope. Increased funding directed to certain focused autoimmune disease research activities and initiatives is another alternative. Several focused activities, such as the Autoimmunity Centers of Excellence (ACEs), Accel- erating Medicines Partnership® (AMP®) Program including Autoimmune and Immune-Mediated Diseases (AMP® AIM) and the Immune Toler- ance Network (Chapter 5) are examples of such focused research activ- ities. Funding to further strengthen the autoimmune disease research 1 https://allofus.nih.gov/about/faq (accessed February 25, 2022). 2 https://braininitiative.nih.gov/sites/default/files/pdfs/brain_technical_one_pager _1072022_508c.pdf. PREPUBLICATION COPY—Uncorrected Proofs

422 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE workforce is a focused activity deserving of additional funds. This could be done with input and collaboration with autoimmune disease-specific and professional societies. Advantages to increasing funding include a relatively low adminis- trative burden since they would leverage existing mechanisms. Disadvan- tages include the uncertainty and unpredictability of funding increases that compromises systematic planning for research. Funding increases would be highly contingent on successful advocacy within and outside of NIH, as well as substantial Congressional support. In addition, in the case of limited new resources, there may be opposi- tion to earmarking funding for autoimmune disease research and there may be unhelpful competition among ICs and in autoimmune disease research areas. New investments in one area of research may be offset by cuts in another. If funding is not used for collaborative research activities, siloing of research could be accentuated further. Given these consider- ations, the committee notes that funding by itself is necessary but not sufficient for enhancing the research enterprise for autoimmune diseases; it does not address issues of coordination, prioritization, or workforce development. Option 2a: Coordination by Revitalizing ADCC The ADCC, NIH’s current coordinating mechanism for research on autoimmune diseases, was most active between 1998 and 2005, when it produced reports summarizing the state of autoimmune disease research and funding (2000), an autoimmune disease research plan (2002), and a report on progress made in autoimmune research (2005.) The commit- tee did not identify an implementation plan for the 2005 research plan consisting of goals, strategies, and milestones. Since 2005, reporting to Congress on general progress made on autoimmune disease research has diminished, while the field of autoimmune disease research has expanded and become more complex. The last triennial report to Congress (2016- 2018) provides information on highlights of specific research findings in the areas of understanding the biology of autoimmune disease, autoim- mune diseases and pregnancy, and successes in improving screening, diagnosis, and treatment. Currently, resources supporting the ADCC are limited to two staff members from NIAID who carry out ADCC activities as part of their general work responsibilities. In addition, there is no specific funding dedicated to ADCC activities. Based on public records, the ADCC held one public meeting in 2019 and 2020. Among the advantages of revitalizing the ADCC is that it would not require creating a new entity or developing new relationships within NIH PREPUBLICATION COPY—Uncorrected Proofs

ENHANCING AUTOIMMUNE DISEASE RESEARCH 423 or with external stakeholders. The experiences gained from developing the 2002 research plan can be applied to developing a new, more robust strategic research and implementation plan. A potential disadvantage to revitalizing the ADCC is that it lacks IC neutrality by virtue of its place- ment within NIAID. ADCC also lacks authority and resources to direct or to support the ICs in implementing research associated with a new strategic research and implementation plan. Not only would additional resources be required, but there may be internal reluctance to significantly resource and empower a more robust ADCC. Option 2b: Coordination by Creating an HHS Autoimmune Disease Coordinating Committee One alternative that the Department of Health and Human Services (HHS) has used for complex and crosscutting issues is to elevate these issues beyond NIH or other HHS operating division. This can be done in multiple ways, including by creating an ad hoc committee, an internal coordinating committee, or an advisory committee at the level of the Sec- retary. The committee envisions such a committee as an HHS advisory body designed to convene, share, and potentially develop new strategies to tackle this complex problem. Such a body, located within the Office of the Secretary, would help assure that autoimmune disease research and translation to detection, prevention, and care receive deserved attention at NIH and across HHS units, and that these efforts would fully leverage the capabilities of sister agencies. NIH’s participation in a well-run HHS ADCC would allow NIH ICs to be informed on critical ancillary and often practical real world issues related to autoimmune disease that could be tackled through research. These might include the needs of special populations, including older people, people with disabilities, and racial and ethnic populations. Agen- cies such as the Agency for Healthcare Research and Quality (AHRQ), Centers for Disease Control and Prevention (CDC), Centers for Medicare and Medicaid Services (CMS), Health Resources and Services Adminis- tration (HRSA), Substance Abuse and Mental Health Services Adminis- tration (SAMHSA), as well as the Administration on Aging and Indian Health Service would have specific expertise in these areas. CDC could provide perspectives on public health dimensions of autoimmune dis- ease. CMS and HRSA could provide expertise on health care issues and the Food and Drug Administration could advice on regulation and drug approval. SAMHSA could be informed and benefit from NIH research on co-occurring mental health issues related to autoimmune diseases and could provide information on potential areas needing NIH research. An added benefit of elevating this issue to the cabinet level is that it would PREPUBLICATION COPY—Uncorrected Proofs

424 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE ease and enhance engagement with non-HHS agencies such as the Social Security Administration on disability determinations issues that people with autoimmune disease may confront. While dramatic new policy making or bold research initiatives might not emerge from the work of a cabinet-level crosscutting committee, important exchanges of information could benefit both the NIH research community and sister agencies. One could also presume that affected individuals and advocacy groups would gain a broader appreciation of these issues through public meetings and other communication efforts. On the other hand, creating a new crosscutting HHS ADCC can come with costs, added burdens, and frustrations. The downside of broad engagement can be skepticism, and the risk of a superficial, rote, or dis- engaged response. Discussion can lack depth, nuance, or perceived imme- diate relevance. Cabinet-level engagement also risks politicizing scientific issues. A well-run HHS ADCC would also require staff, funding, and some authority, all of which might be perceived as better spent directly on NIH coordination including enhanced research to fill critical gaps. While the committee believes NIH would benefit from engaging more with sister agencies, it may be that there are less formalized and more issue-specific ways of doing this than the creation of a new HHS body. Option 3: Develop a Congressionally Mandated National Autoimmune Diseases/Autoimmunity Research Plan The committee considered and believes that there may be significant value in a congressionally mandated National Autoimmune Diseases/ Autoimmunity Research Plan that could be sited in any one of a number of organizational entities. There is useful precedent for such a plan, per- haps most notably the National Plan to Address Alzheimer’s Disease (AIM, 2021). NIH is an active participant in providing input to and implement- ing the National Plan. Through the AD+ADRD Research Implementation Milestones database,3 NIH describes its Alzheimer’s research efforts in response to the National Plan’s research framework, detailing specific steps and success criteria toward achieving the National Plan’s goals. The mile- stones also note funding initiatives, accomplishments, and highlights of progress toward accomplishing the National Plan goals. Congress receives an annual report updating the progress made toward achieving National Plan goals (HHS, 2020). While no analogy between diseases or the state of research for two conditions is ever perfect, there are similarities between Alzheimer’s and certain autoimmune diseases in terms of the significant numbers 3 Available at https://www.nia.nih.gov/research/milestones. PREPUBLICATION COPY—Uncorrected Proofs

ENHANCING AUTOIMMUNE DISEASE RESEARCH 425 of individuals affected. For example, the estimated number of affected individuals living with Alzheimer’s disease is 5.1 million (HHS, 2020), compared to an estimated 14.7 to 23.5 million individuals living with at least one autoimmune disease (NIH, 2005). Yet, understanding of both Alzheimer’s disease and autoimmune disease conditions is limited. In some cases, research is in its infancy, treatments are limited, and there are no cures. Most importantly, no overall architecture for Alzheimer’s disease research existed before developing the National Plan, and one does not exist for autoimmune disease research. The committee believes that Congress would have to take specific actions for such a plan to yield results. First, those individuals assem- bling the plan would have to review this committee’s and other efforts in order to describe and fully analyze the research portfolio and identify strengths, challenges, and gaps. Second, those assembling the plan would have to devise a process for assembling and executing a plan. This would involve consulting with of internal and independent experts from diverse fields, providing substantial opportunities for public engagement and input, regular, detailed updating on progress, one or more summits as part of the process. But most importantly, it would set specific priorities, detailed objectives within those priorities, metrics for evaluating progress, and milestones. Progress reporting would go beyond merely cataloging substantial scientific advances in response to plan goals and objectives. Rather, it would include detailed descriptions of advances that scientists, stakeholders, and other lay people could understand and contextualize. There are several advantages to a properly conceived and executed plan. First, it brings the imprimatur of Congress, which in turns brings weight, attention, expectation of results, and likely resources. Those fund- ing, overseeing, and otherwise taking a special interest in NIH autoim- mune disease research would have a specific stake in achieving certain concrete objectives and outcomes. Moreover, they and other stakeholders would be able to see, and in the case of the public, participate in a process for developing a plan and monitoring its progress and outcomes. Second, the process would almost certainly enhance communication, coordination, and collaboration, both by virtue of the process and by what it generates. Third, the process would involve a creative review of alternative research paradigms for accelerated progress. These paradigms might suggest new ways of doing business or meta-projects. Fourth, and relatedly, the process of developing a plan might well stimulate research- ers to propose, examine, and be funded for new lines of inquiry. Fifth, it might provide a sense of hope to sufferers and their families that progress is being made in a structured and measurable manner. Efforts that engage the public and offer real transparency often have the ancillary benefit PREPUBLICATION COPY—Uncorrected Proofs

426 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE of demystifying the scientific enterprise and building confidence in the endeavor. This option is not without potential disadvantages. If not properly structured, progress can give way to process. A plan can raise expecta- tions unreasonably, and focusing on predetermined goals and objectives might cause leaders and researchers to be less attentive to complemen- tary, relevant science and research that is happening peripherally or in other domains. NIH’s default and highly successful modus operandi, and its remarkable results, often rest more on investigator-initiated research rather than top-down research. Option 4: Create a New National Institute of Autoimmune Disease and Autoimmunity Research The general mission of ICs is to support NIH’s overall mission “to seek fundamental knowledge about the nature and behavior of living sys- tems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.” ICs also support the training of basic and clinical scientists to carry out research and disseminate informa- tion on research progress to the public. The committee considered the creation of a new National Institute of Autoimmune Disease and Autoimmunity Research (NIADAR) that would support and drive innovative, crosscutting autoimmune disease and autoimmunity research through intramural and extramural pro- grams, as well as promote and support the training of an autoimmune disease workforce. Such an institute would have significant advantages. A new institute would likely elevate the visibility and status of autoimmune disease within NIH and externally; and it would assure a high-level, constant, broad, and detailed focus on autoimmune disease research. NIADAR would establish a clear focal point for autoimmune disease research for individuals within NIH and for external constituencies. The Institute would function as a clear and empowered convener, coordinator, and accountable focal point for autoimmune disease and autoimmunity research. To a greater extent than other options considered by the committee, certain critical success factors would need to be addressed for this effort to succeed. A new but underfunded, undefined, weak, or neglected Institute is less desirable than a somewhat diffused effort in well-established and highly functioning ICs. Even if those factors were overcome, establishing a new institute would come with a number of disadvantages. Creating a new IC is by definition administratively daunting and would require congressional action. Creating a new IC would also require a long-term view and patience, neither of which may hold appeal to those anxious PREPUBLICATION COPY—Uncorrected Proofs

ENHANCING AUTOIMMUNE DISEASE RESEARCH 427 for progress. Thus, creating a new IC comes with high transaction and opportunity costs, and it could initially increase duplication of effort and even distract from productive research efforts. It might even cause confu- sion during an initial period of transition. While reorganizations can bring key people together “under one roof,” they inevitably dislocate key people as well. Moreover, creation new units could engender resistance and resentment from existing enti- ties, neither of which advances the research enterprise. Finally, creat- ing a new Institute risks unrealistically raising expectations about focus, resources, and research outcomes. Option 5: Creation of Office of Autoimmune Disease/ Autoimmunity Research within the Office of the Director The committee carefully considered the option of creating an Office of Autoimmune Disease/Autoimmunity Research (OAD/AR) within the OD. The committee found significant merit in this option, provided NIH pursued this option in a way in that would likely succeed. This option is not a new one and was proposed in a bill advanced by then Senator Joe Biden in 1999. The committee found that the 1999 bill addressed several concerns that the committee had raised in its deliberations including the need for a central entity to: promote coordination and cooperation among ICs and other entities, develop an agenda for conducting and support- ing autoimmune disease research, promote the appropriate allocation of NIH for autoimmune disease research, report on research activities and identify future research opportunities, and to provide leadership on auto- immune disease to HHS, the NIH Director and other relevant agencies. As governmental units at NIH and elsewhere persuasively argue to the Congress, the impact of a research organization is likely to correlate with the extent to which it owns and controls resources. This is particu- larly true in the case of new entities negotiating and advising over the activities of multiple actors who are already resourced. Given this, the committee considered two configurations for OAD/AR. In the first, OAD/ AR would have its own research budget and it would substantially con- trol certain key budgetary decisions about autoimmune disease research activities conducted elsewhere in NIH, the Office of AIDS Research serves as a model for this configuration. In the second configuration, while the Office would have certain responsibilities, it would receive only modest or limited resources or authority to carry them out; the Office of Research on Women’s Health serves as a model for this configuration. The commit- tee recommends the former, fully recognizing that budgetary control is among the most sensitive issues within any organization. The committee recognizes that this effort might need to strike some middle ground. PREPUBLICATION COPY—Uncorrected Proofs

428 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE Success will also depend on tailoring OAD/AR to specific and man- ageable objectives. Furthermore, a successful crosscutting office needs the capacity to suggest and advance creative new scientific approaches, partners, and paradigms. While effective offices recognize the importance of living within institutional cultures and constraints, they can still sug- gest and direct new ways of doing business that others may not see, have the time or expertise to consider, or the resources to carry out. This, in the committee’s view, is how a new OAD/AR within the OD would provide its greatest value. As noted above, the committee believes successfully implementing any option will depend on careful attention to budget considerations and a variety of other factors critical to success--a substantive and serious focus, a clearly defined strategic vision, and a well-considered level of support for funding and staff. Absent such determinants of success, the committee believes the creation of such an office would not be a fruitful effort. Because NIH is an institution with world-class expertise, billions of dollars in resources, and extraordinarily high standards, no one benefits when a new organization is created that does not meet those standards. In arriving at this conclusion, the Committee has considered various organizational models for creating an office meeting such standards by examining other offices within the Office of the NIH Director. Based on these reviews, the Committee concludes that the Office of AIDS Research can provide a highly desirable model for a new Office of Autoimmune Diseases/ Autoimmunity Research. This organizational model has pro- vided such important elements for coordinating HIV and HIV-related research through: • Advice provided to the Director of NIH, HHS and other entities on HIV and HIV-related research; • Establishment of research priorities/goals; • Development and annual evaluation of strategic plan for HIV and HIV-related research throughout NIH; • Assurance that funds are invested in the areas of scientific priority and allocates such funding; • Oversight, coordination and management of HIV and HIV-related research (scientific, budgetary, legislative, and policy) in collabo- ration with other NIH entities (ICs participate in Office advisory bodies); • Convening stakeholders, encouraging collaboration and catalyz- ing innovation to address emerging scientific and public health challenges; and • Including attention to workforce development in strategic goals for HIV and HIV-related research. PREPUBLICATION COPY—Uncorrected Proofs

ENHANCING AUTOIMMUNE DISEASE RESEARCH 429 Such activities in OAR have led to advances in HIV and HIV-related research ranging from prevention of HIV through a long-acting inject- able (incabotegravir) and risk reduction for HIV infection via use of a microbicide (dapivirine) in an intravaginal ring (Office of AIDS Research, 2021). As a central coordinating office it has been uniquely situated to handle emerging trends and challenges such as the SARS-CoV-2/COVID- 19 pandemic by applying knowledge from HIV science. From 2016 to 2021, the NIH HIV research program identified and communicated how HIV research could contribute to an understanding of the COVID-19 pan- demic and considered mitigation strategies to assure that the conduct of HIV research would not be negatively affected by the COVID-19 experi- ence. As another example, when SARS CoV-2/COVID-19 emerged, OAR employed internal and external partnerships to develop and disseminate clinical guidelines addressing COVID-19 and HIV. OAR capitalized on the HIV/AIDS Trials Networks to support the pursuit of promising pre- vention and treatment approaches for COVID-19 through clinical trials (Office of AIDS Research, 2021). In the area of workforce development, OAR and ICs launched an initiative for inclusion of women and underrepresented populations in the HIV research workforce of the future (Office of AIDS Research, 2021). Using the OAR as a model, the committee believes that a well-con- figured OAD/AR could be an essential ingredient in further stimulat- ing promising and impactful autoimmune disease and autoimmunity research at NIH that can be translated into clinical practices that will prevent autoimmune diseases from occurring or that will improve the lives of those living with autoimmune disease. The Committee envisions the following responsibilities for the Office: A. The Office would devise a process for and lead the collaborative development of a Strategic Plan to address opportunities and gaps in scientific knowledge. This would result in an NIH Strategic Plan for Autoimmune Disease and Autoimmunity Related Research. The plan would: 1. Establish both a high-level blueprint and a more detailed research agenda. 2. Set both high-level national priorities and detailed disease- specific and crosscutting priorities. 3. Describe a detailed research program and implementation plan for carrying out that agenda. 4. Work with ICs to identify and promote research opportu- nities that align with strategic plan goals (e.g. developing solicited RFAs for crosscutting research grants, promoting PREPUBLICATION COPY—Uncorrected Proofs

430 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE Small Business Innovation Research (SBIR) and Small Busi- ness Technology Transfer (STTR) Programs grants). 5. Address autoimmune disease research workforce and training issues, including diversity of the workforce. 6. Provide metrics for evaluating progress and a process for applying those metrics. 7. Examine scientific and organizational barriers to break- throughs and potential solutions. In developing and implementing the strategic plan, the Office would actively seek the collaboration and engagement of IC intramural and extramural investigators and other stakeholders. This outreach would serve to catalyze innovation and identify emerging areas of research opportunity. Strengthening outreach could also inform funding for other important research priorities undertaken by various ICs. In support of strategic planning, the Office, in collaboration with ICs and other stakeholders, should develop a consensus vocabu- lary that includes both clinically defined autoimmune diseases and autoimmune mechanisms and a list of autoimmune dis- eases. Such a definition and list of diseases is critical to improve research, data collection, guide patient care, and coordinate com- munication. Periodic reassessment of the definition and listing of autoimmune diseases, should be undertaken based upon emerg- ing data. B. The Office would ensure that funds are invested in the areas of highest scientific priority. The Office would: 1. Engage in developing detailed autoimmune disease research budgets. 2. Set budgetary priorities and attempt to align available dollars. 3. With its own resources fund certain activities including those that are crosscutting; high risk/reward; relevant to special populations; and related to workforce development. C. The Office would provide scientific coordination and manage- ment of the research program. This would include: 1. Serving as a focal point for external parties seeking infor- mation or providing input on autoimmune disease research opportunities at NIH. 2. Serving as a convener for emerging and crosscutting sci- ence on autoimmune disease. Collaborating with organi- zations focused on persons-centered research, such as the PREPUBLICATION COPY—Uncorrected Proofs

ENHANCING AUTOIMMUNE DISEASE RESEARCH 431 Patient-Centered Outcomes Research Institute, and other stakeholders, including industry, disease organizations, patient advocates, and patients and their families in priority setting and research design. 3. Stimulating novel approaches to autoimmune disease research. 4. Leveraging existing efforts and develop synergies across mul- tiple Institutes, Centers, and scientific disciplines. 5. Coordinating with the Center for Scientific Review to review assignment guidelines to ensure that autoimmune diseases grants are assigned to the appropriate study sections with optimal representation of experts and expertise, including expertise for reviewing basic science (i.e., tissue culture, ani- mal, translational) and human studies, and evaluate assign- ment guidelines on an ongoing basis. 6. Coordinating existing autoimmune disease data collection systems and biorepository resources across NIH; creating a database of such resources to facilitate research collabora- tion, and coordinating with external databases that may have useful data (e.g. the VA Million Veterans Program, the UK Biobank and industry biorepositories). 7. Coordinating autoimmune disease research across other HHS agencies and other federal agencies (e.g., AHRQ, CDC, FDA) to promote cohesion in efforts to advance generation of knowledge and care delivery for autoimmune disease. D. The Office would conduct or contract for evaluations of ongoing efforts. E. The Office would produce annual reports on the progress made on autoimmune disease research activities for the Congress. Annual congressional reports can provide key information on priorities and outcomes to enable policymakers to assess the level of funding for autoimmune disease research. Others who could benefit from such information are key stakeholders in the autoim- mune research enterprise and members of the public. F. Building on this report and other relevant reviews, the Office would lead the development of an enhanced information sys- tem for autoimmune disease research. The committee’s efforts revealed challenges that researchers and policy-makers may face in easily accessing, synthesizing, and analyzing relevant research opportunities and results. The committee believes that, consistent with NIH’s existing and excellent information systems, more can PREPUBLICATION COPY—Uncorrected Proofs

432 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE be done to allow researchers ready but refined access to research opportunities and ongoing research efforts. Creating OAD/AR comes with substantial advantages. Virtually all of the advantages enumerated above regarding the creation of an Insti- tute would apply. For example, an Office would raise visibility, provide sustained leadership, and establish a clear focal point for autoimmune disease research within NIH and externally through extramural, intramu- ral, training, communication and outreach activities. An Office properly constituted and supported could even be leaner and more agile than an Institute. Proximity to the NIH Director brings obvious advantages, including influence, visibility, and status. Furthermore, the Office would benefit from interactions and collaborations with other NIH OD Offices and would be positioned to identify and leverage other NIH-wide research activities that align with the autoimmune disease research agenda. The Office would both bring and benefit from a crosscutting, independent perspective that would allow more objective priority setting, measure- ment and evaluation. OAD/AR would independently advocate for and promote transpar- ency; and it would establish a framework for accountability among rel- evant Institutes. This would build goodwill among stakeholders that in turn, would strengthen support for the research endeavor. Finally, fewer costs and controversies generally come with creating Offices than with creating new Institutes. The committee acknowledges that beyond the caveats raised in the introduction above, creating an Office is not without potential challenges. First, though more modest than those required by a new Institute, creating a new Office would require significant resources for infrastructure, robust staffing, and the capacity to function nationally and internationally as a convener, broker, and communication hub. Second, it would likely require new funding to stimulate new crosscutting and collaborative autoim- mune disease research and enhance workforce development. Third, the more authority and resources it is granted, the more opposition it may encounter. Opposition may bring some disruption, some of which may be unproductive, and resistance that may undercut collaboration. On balance, the committee believes that the advantages of creating an Office significantly outweigh the disadvantages. Such an office has poten- tial promise and impact in expanding both the frontiers and near-term impacts of autoimmune disease research. The committee believes that creating OAD/AR is the best alternative for strengthening autoimmune disease research at NIH. PREPUBLICATION COPY—Uncorrected Proofs

ENHANCING AUTOIMMUNE DISEASE RESEARCH 433 RECOMMENDATIONS As discussed above, the committee considered five options for enhanc- ing autoimmune disease research and resulting outcomes: increased funding, two options for coordinating research, establishing a national strategic plan, establishing a new institute, and creating a special office for autoimmune disease research. With the caveats noted above, the com- mittee believes that a well-configured Office of Autoimmune Disease/ Autoimmunity Research could be an essential ingredient in further stimu- lating promising and impactful autoimmune disease and autoimmunity research at NIH that can be translated into clinical practices that will pre- vent autoimmune diseases from occurring or that will improve the lives of those living with autoimmune disease. Recommendation 1: The Director of the NIH should create an Office of Autoimmune Disease/Autoimmunity Research within the Office of the Director. Acknowledging that creating an of Office of Autoimmune Disease/ Autoimmunity Research may take some time, the committee makes two specific recommendations related to data collection that could be imple- mented independent of the Office by ICs, one independently and the other in collaboration with other ICs.  First, progress on autoimmune disease requires substantially more sophisticated and refined epidemi- ology on the individual and aggregate burden of autoimmune disease. The extant knowledge base is growing, but there are important gaps, including trends with respect to incidence and prevalence, comprehensive evaluations of the burden (including direct and indirect costs) and of the risk factors for these diseases, the impact on different populations, and the trajectory of these diseases from the period before disease manifests and through the life course, and the impact of specific treatments and interventions. The committee found a lack of long-term (20 years or more) popula- tion-based epidemiology studies on autoimmune disease.  Such studies would allow for assessing trends, identifying differences among popu- lation subgroups, and in determining the prevalence and incidence of under-researched autoimmune diseases and conditions, such as celiac disease. The National Cancer Institute’s Surveillance, Epidemiology, and End Results Program, which provides information on cancer incidence and survival in the United States is a model for such studies already exists at NIH. PREPUBLICATION COPY—Uncorrected Proofs

434 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE Recommendation 2: The NIH should establish long-term systems to collect and ensure optimum usability of population-based sur- veillance and epidemiological data (e.g., incidence, prevalence) on autoimmune diseases and measures of autoimmunity (e.g., autoan- tibodies, inflammation) and support the optimization of existing data sources. The committee also found that few studies exist that are able to provide information on the long-term progression of autoimmune dis- ease beginning in the period before disease manifests through the life course. Such studies would allow for a greater understanding of the het- erogeneity of disease expression and changes with time and over various life stages. Such studies could be designed to address wide variety of disease outcomes and health effects. Establishing population cohorts is critical for studying mechanisms leading to autoimmune diseases. Early life exposures and timing of these exposures influence health at different life stages at a population and individual patient level. Autoimmune diseases are long-lasting, and heterogeneous conditions for which manifestations and coexisting mor- bidities change over time. It is essential to support long-term (10–20+ years) patient cohort studies. Such studies would provide understand- ing of opportunities for developing clinical treatments and behavioral interventions. Recommendation 3: The NIH should support the development of population cohorts that extend from the period before disease manifests to the development of symptoms and disease, and should support patient cohorts that will allow the examination of the pro- gression, coexisting morbidities, and long-term (20+ years) out- comes of autoimmune diseases. Data collection should include, but need not be limited to: • Genome-wide association • Environmental and occupational exposures such as respirable silica, vitamin D and iodine, viruses, and smoking • Autoantibody, cytokine, and T cell assays, particularly in new- onset disease • Response to therapeutic interventions, including timing of treat- ment (e.g., to assess whether early treatments prevent disease progression) • Development of co-occurring autoimmune diseases. Finally, to address the research gaps outlined throughout this report, a comprehensive national research agenda for autoimmune diseases is PREPUBLICATION COPY—Uncorrected Proofs

ENHANCING AUTOIMMUNE DISEASE RESEARCH 435 required. Achieving this objective will require coordination and collabo- ration among researchers, research groups, and stakeholders as well as the dedicated pursuit of research that: defines autoantibodies that pre- dict and diagnose autoimmune diseases; identifies common mechanisms in inflammation; determines gene-environment interactions within and across autoimmune diseases; examines the role of environmental expo- sures on autoimmune diseases; elucidates disparities and their determi- nants; determines the impact of coexisting morbidities and complications of autoimmune diseases on clinical outcomes, functional outcomes, qual- ity of life and health care utilization; and explores the effect of interven- tions to mitigate impact of coexisting morbidities and complications for patients with autoimmune disease across the lifespan. During the course of researching Chapters 3 and 4, the committee assembled a list of research needs based on committee judgment. The list below is not intended to be comprehensive. However, it is indicative of the kinds of research needed, and by itself is far-reaching in terms of the kinds of research and disciplines required as well as the many diseases included in the autoimmune disease category. The committee believes that a robust effort will be required to coordinate creation of a comprehen- sive national research agenda that incorporates the thinking of associated ICs and other stakeholders, and as such illustrates the role that an Office of Autoimmune Disease/Autoimmunity Research could fill as no other currently existing entity could. Recommendation 4: The NIH should provide funding and support for a national research agenda that addresses key gaps identified by the committee. Prioritized research streams should include, but need not be limited to, clinical and basic research that addresses the research streams below. Heterogeneity in autoimmune diseases takes many forms, which could range from differences in symptom presentation and disease pro- gression, as seen in persons with systemic lupus erythematosus, to sever- ity of disease, as observed in myocarditis in men compared with women, to varying responses to the same therapy. Dissect heterogeneity across and within autoimmune diseases to decipher common and disease-specific pathogenic mechanisms. • Examine common innate inflammatory pathways (e.g., damage- associated molecular patterns, pathogen-associated molecular patterns, pattern recognition receptors, inflammasomes, and associated signaling pathways), dysregulated cellular processes, and altered metabolism across multiple autoimmune diseases to PREPUBLICATION COPY—Uncorrected Proofs

436 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE understand the biologic mechanisms underlying development, progression, remission, and exacerbation of autoimmune diseases in children and adults • Apply machine learning methods that combine layers of “omics” data (e.g., genomics, proteomics, metabolomics) to generate new mechanistic hypotheses and inform discovery of novel drug targets • Elucidate mechanisms by which sex-specific factors (such as hor- mones, X and Y chromosomes, birth control products, endocrine disrupting chemicals) influence autoimmune disease, examining the effect of puberty, pregnancy, and menopause to understand sex differences in autoimmune diseases • Identify autoantigens across autoimmune diseases using new technologies that allow T cell receptors identified by single cell RNA sequencing from tissue to be interrogated without bias transfecting mRNA libraries into reporter antigen presenting cells • Dissect molecular mechanisms associated with poor outcomes • Design research that bridges animal models and human studies to better understand common mechanisms in inflammation for specific autoimmune diseases Researching less common autoimmune diseases can be difficult owing to smaller pools of persons affected. At the same time, identifying genetic variants, for example, could reveal insights that might be applied to more common diseases. Persons suffering from rare diseases that are associated with severe illness and or/early mortality are of particular concern. Study rare autoimmune diseases and develop supporting animal models. • Study autoimmune diseases that affect fewer individuals but often have a high morbidity/earlier mortality to reveal novel, shared, or dominant molecular pathways and novel or improved therapeutic options - Dominant pathways in the less common autoimmune diseases may reveal shared molecular pathways with other autoim- mune diseases to facilitate drug-repurposing, rapid trials and possible therapies that could rapidly impact clinical care • Develop animal models to better understand the mechanisms of rare autoimmune disease Chapter 4 reviewed a variety of signals being explored as biomark- ers to predict disease, confirm diagnosis, and predict flares of disease. PREPUBLICATION COPY—Uncorrected Proofs

ENHANCING AUTOIMMUNE DISEASE RESEARCH 437 Further investigation of these and novel signals can inform preventive and therapeutic strategies. Define autoantibodies and other biomarkers that can diagnose and predict the initiation and progression of autoimmune diseases. • Determine the pathophysiological relationship of antibodies to autoimmune disease—for example, which autoantibodies are biomarkers of autoimmune diseases, which are effectors, and the reasons for the differences • Determine the temporal relationship of antibodies to autoimmune disease—for example, how and why some autoantibodies appear decades before clinical illness and others appear simultaneously with first symptoms • Understand differences in autoantibody profiles by age, sex, and sex-and-age, race, ethnicity, and ancestry, for individual autoim- mune diseases and in relation to their ability to predict and diag- nose autoimmune disease • Examine whether infections (e.g., SARS-CoV-2) and/or chemicals (e.g., bisphenol A) influence autoantibody levels/types and/or immune complex formation that are diagnostic or pathological for autoimmune diseases • Explore the pipeline for development and validation of autoanti- bodies as disease biomarkers and surrogate endpoints of disease • Identify novel biomarkers and complex “signatures” that predict and diagnose autoimmune diseases including cytokines, microR- NAs and other markers As discussed in Chapter 2 and Chapter 4, genetics, and particularly gene variants, environmental exposures, and timing interact to increase or blunt an individual’s susceptibility to autoimmune diseases. Identifying the biological functions of gene variants and the effects of environmental exposures on their functions over time could reveal new avenues for care. Determine the biologic functions of genetic variants and gene– environment interactions within and across autoimmune diseases using novel, cutting-edge technologies. • Study early-onset (e.g., childhood-onset) and rare autoimmune diseases to identify pathologic genetic variants and potential mechanistic insights • Systematically map genetic variants of individual autoimmune diseases to biologic functions in different populations in order to (1) translate genotype to phenotype, (2) define immune pathways PREPUBLICATION COPY—Uncorrected Proofs

438 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE that may predict response to treatment, and (3) inform under- standing of the effect of environmental exposure in autoimmune diseases • Understand genomic and pharmacogenomic data as they relate to the individual, that are disease specific, or provide insight across multiple autoimmune diseases • Explore chimeric antigen receptor-T cell/natural killer cell thera- pies to benefit immune regulation • Use and improve artificial intelligence, computational science, and other technologies to understand gene–environment interactions Social determinants of health such as trauma, including cumulative childhood stress as a result of adverse childhood experiences (ACEs), can increase the risk of autoimmune disease (Dube et al., 2009; Roberts et al., 2017). Similarly, the trauma and the dust clouds of the September 11, 2001 attack have been implicated in the increased risk of systemic autoimmune disease in exposed persons (Miller-Archie et al., 2020). The mechanisms by which social determinants and environmental exposures act alone and together to affect the risk for and course of autoimmune disease over the life span should be investigated using systematic approaches whenever possible. Examine the role of environmental exposures and social determi- nants of health in autoimmune diseases across the lifespan. • Systematically examine the effect of environmental exposures (e.g., chemical, infectious, dietary) and social determinants of health in children and adults, including stress, for individual and/or multiple autoimmune diseases, including disease flares • Determine the effect of environmental exposures on immune pathways in patients and animal models of autoimmune disease • Utilize a life-course approach along with advanced methodolo- gies (e.g., computational science) to identify and examine the potential effect of interacting co-exposures that may increase sus- ceptibility to disease, and to understand how these factors affect onset, progression, and severity of disease • Conduct a systematic investigation of the effects of nutrients, dietary antigens, exercise, aging, and microbiome in normal tis- sue development and homeostasis in the pre-clinical phase of disease and during disease and recovery • Explore novel methodologies to identify distinct and interacting biological and biopsychosocial factors contributing to observed sex/gender differences in autoimmune diseases, including the PREPUBLICATION COPY—Uncorrected Proofs

ENHANCING AUTOIMMUNE DISEASE RESEARCH 439 effect of puberty, menopause, and pregnancy on autoimmune diseases As indicated in Chapters 3, and 4, individuals frequently develop more than one autoimmune disease at a time as well as complications and other morbidities. The data on co-occurring autoimmune diseases focuses only on a limited number of diseases. Evaluating the epidemiology and risks for developing other morbidities, identifying those at greatest risk, assessing the impacts of coexisting morbidities, and interventions to pre- vent or ameliorate these could greatly improve patient care. Determine the impact of coexisting morbidities, including co-occurring autoimmune diseases and complications of autoimmune diseases, across the lifespan, and develop and evaluate interventions to improve patient outcomes. • Investigate the occurrence of and risk factors for disease com- plications (e.g. functional impairment, disability, growth impair- ment), co-occurring autoimmune diseases, coexisting morbidities (e.g., cardiovascular disease, cancer), and psychosocial conditions (e.g., fatigue, depression, pain) • Investigate the effects of complications and coexisting morbidities on clinical outcomes (e.g., adherence to therapy, disease activity, disease damage), functional outcomes (activity and participation in daily and community life, education and work status), health- related quality of life, and healthcare utilization and costs. • Conduct research to improve understanding of the long-term consequences of autoimmune diseases in children • Develop and test treatment models, targeting those at highest risk, that prevent, detect, and address complications and coexist- ing morbidities in persons living with autoimmune disorders, incorporating chronic disease self-management strategies and other approaches • For complications for which there are no highly effective treat- ments, such as pain and fatigue, develop, identify, and test new therapies • Develop and test interventions to improve or address lack of or inadequate social support in order to improve symptom and disease management and daily life, including interventions for parents of children with autoimmune disorders There are disparities in who develops autoimmune diseases as well as how the diseases progress; among the causes for disparities are differ- ences in living environments, access to and affordability of care, and even provision of care. Researchers have observed, for example, that Hispanic PREPUBLICATION COPY—Uncorrected Proofs

440 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE patients and patients in the U.S. South with autoimmune disease-related kidney failure are less likely to receive kidney transplants than non-His- panic patients or patients in the U.S. West and Northwest (Costenbader et al., 2011; Knight et al., 2014). Research to identify the causes of and risks of disparities, interventions to mitigate them, and the most effective way to implement mitigations is needed, particularly in groups who receive suboptimal care and are underrepresented in clinical populations. Foster research to advance health equity for all autoimmune disease patients. • Investigate genetic, biological, social determinants, and environ- mental mechanisms of autoimmune diseases in different racial, ethnic, and other underrepresented groups, as well as across sexes and over the lifespan • Identify individuals at high risk of autoimmune diseases and implement prevention strategies • Investigate disparities and determinants of disparities in disease stage at presentation and progression of disease, including com- plications, coexisting morbidities, functional impairments, and disability • Explore novel methodologies to identify distinct and interacting biological and biopsychosocial factors contributing to observed sex differences in autoimmune diseases • Collaborate with consumers, community-based organizations, and other partners to develop and evaluate health care delivery and/or policy interventions to address identified disparities and generate evidence to support their feasibility, sustainability, and dissemination • Build long-term partnerships between patients, communities, cli- nicians, and scientists to increase participation of underserved populations in interventional clinical trials and other clinical and translational research studies • Conduct dissemination/implementation research to determine best practices and to improve outcomes for all • Conduct research on how to increase recruitment of underserved populations in clinical research, and in interventional clinical tri- als in particular • Conduct research on how best to target interventions for patients with worse outcomes and/or underserved populations Chapter 2 noted the rates of many autoimmune diseases are rising. Chapter 3 revealed that there are inadequate data on the financial costs of autoimmune diseases. For diseases where good data are available such as inflammatory disease and celiac disease, the estimated costs are high. PREPUBLICATION COPY—Uncorrected Proofs

ENHANCING AUTOIMMUNE DISEASE RESEARCH 441 As these costs will impact public health budgets, research to define costs should be undertaken as findings could inform research priorities. Assess the direct and indirect costs of autoimmune diseases. • Examine insurance claim data to assess inpatient, emergency room, outpatient, physician visit, pharmacy (including dispari- ties between different therapies), laboratory, and medical device costs associated with autoimmune diseases • Examine the costs of lost wages, job turnover, and other work- productivity issues • Examine the costs of premature mortality • Examine the costs of associated home care and child care REFERENCES AIM (Alzheimer’s Impact Movement). 2021. Fact sheet: National Plan to Address Alzheimer’s Disease. https://alzimpact.org/media/serve/id/5ce4d095edf7e#:~:text=The%20Na- tional%20Alzheimer’s%20Project%20Act%20(Public%20Law%20111%2D375),from%20 outside%20the%20federal%20government (accessed December 7, 2021). Costenbader, K. H., A. Desai, G. S. Alarcón, L. T. Hiraki, T. Shaykevich, M. A. Brookhart, E. Massarotti, B. Lu, D. H. Solomon, and W. C. Winkelmayer. 2011. Trends in the inci- dence, demographics, and outcomes of end-stage renal disease due to lupus nephritis in the us from 1995 to 2006. Arthritis and Rheumatism 63(6):1681-1688. https://doi. org/10.1002/art.30293. Dube, S. R., D. Fairweather, W. S. Pearson, V. J. Felitti, R. F. Anda, and J. B. Croft. 2009. Cu- mulative childhood stress and autoimmune diseases in adults. Psychosomatic Medicine 71(2):243-250. HHS (Health and Human Services). 2020. National Plan to Address Alzheimer’s Disease: 2020 update. https://aspe.hhs.gov/sites/default/files/migrated_legacy_files//197726/ NatlPlan2020.pdf (accessed March 19, 2022). Knight, A. M., P. F. Weiss, K. H. Morales, and R. Keren. 2014. National trends in pediatric systemic lupus erythematosus hospitalization in the United States: 2000-2009. Journal of Rheumatology 41(3):539-546. https://doi.org/10.1097/PSY.0b013e3181907888. Miller-Archie, S. A., P. M. Izmirly, J. R. Berman, J. Brite, D. J. Walker, R. C. Dasilva, L. J. Petrsoric, and J. E. Cone. 2020. Systemic autoimmune disease among adults exposed to the September 11, 2001 terrorist attack. Arthritis & Rheumatology 72(5):849-859. https:// doi.org/10.1002/art.41175. NIH (National Institutes of Health). 2005. Progress in Autoimmune Disease Research, Autoim- mune Disease Coordinating Committee Report to Congress. Office of AIDS Research. 2021. Office of AIDS research congressional justification FY 2022. https:// www.oar.nih.gov/sites/default/files/OAR-FY-2022-CJ-Chapter-FINAL-6.2.2021-508. pdf (accessed 2022, March 4). Roberts, A. L., S. Malspeis, L. D. Kubzansky, C. H. Feldman, S.-C. Chang, K. C. Koenen, and K. H. Costenbader. 2017. Association of trauma and posttraumatic stress disorder with incident systemic lupus erythematosus in a longitudinal cohort of women. Arthritis & Rheumatology 69(11):2162-2169. https://doi.org/10.1002/art.40222. PREPUBLICATION COPY—Uncorrected Proofs

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Autoimmune diseases occur when the body's immune system malfunctions and mistakenly attacks healthy cells, tissues, and organs. Strong data on the incidence and prevalence of autoimmune diseases are limited, but a 2009 study estimated the prevalence of autoimmune diseases in the U.S. to be 7.6 to 9.4 percent, or 25 to 31 million people today. This estimate, however, includes only 29 autoimmune diseases, and it does not account for increases in prevalence in the last decade. By some counts, there are around 150 autoimmune diseases, which are lifelong chronic illnesses with no known cures. The National Academies of Sciences, Engineering, and Medicine was asked to assess the autoimmune disease research portfolio of the National Institutes of Health (NIH).

Enhancing NIH Research on Autoimmune Disease finds that while NIH has made impressive contributions to research on autoimmune diseases, there is an absence of a strategic NIH-wide autoimmune disease research plan and a need for greater coordination across the institutes and centers to optimize opportunities for collaboration. To meet these challenges, this report calls for the creation of an Office of Autoimmune Disease/Autoimmunity Research in the Office of the Director of NIH. The Office could facilitate NIH-wide collaboration, and engage in prioritizing, budgeting, and evaluating research. Enhancing NIH Research on Autoimmune Disease also calls for the establishment of long term systems to collect epidemiologic and surveillance data and long term studies (20+ years) to study disease across the life course. Finally, the report provides an agenda that highlights research needs that crosscut many autoimmune diseases, such as understanding the effect of environmental factors in initiating disease.

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