7

Opportunities and Options for Enhancing Autoimmune Disease Research at NIH

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 the National Institutes of Health (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 specific 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 scientific advances have blurred the definition of autoimmune disease, there is no consensus on the best terms or methods to conceptualize autoimmune disease to meet the differing views and purposes of basic and clinical research, and there is no consensus regarding the number of

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 epidemiologic data on the incidence and prevalence of autoimmune diseases. There is no mandatory reporting system or national registry for autoimmune diseases in the United States. Existing incidence and prevalence data often come from other countries that have health care systems covering the entire population. In the United States, data are incomplete and often outdated, which can limit the ability to assess whether progress has been or is being made in reducing the burden of these diseases.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 diseases, information is lacking on how best to target therapies to individuals. 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 hypotheses. 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 NIH.

Chapter 5 describes the NIH research grant process and coordination of autoimmune disease research. The committee found that the Autoimmune Disease Coordinating Committee (ADCC) has no dedicated funding or staff and functions as a convener of Institutes and Centers (ICs)

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 activity undertaken by ICs across NIH. Committee members reviewed IC strategic plans, websites, and other information to obtain insights into the autoimmune disease 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 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 autoimmune 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 autoimmune 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 autoimmune disease research grants are investigator initiated. The committee notes that in the NIH Research, Condition, and Disease Category (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 disease, depression, eye disease and disorders) 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.

The analysis of the focus of autoimmune disease grants using different methods provided limited information. The committee had no basis upon which to determine whether (1) the funded grants represent 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 disease research workforce. A crosscutting strategic plan to guide current research activities with details on specific goals, objectives, timelines, 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 earlier 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 to 2020 indicates an average of four or fewer IC collaborations during the period. Based on this finding, 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 accomplishments associated with funded research on autoimmune disease. This effort included a high-level examination of clinical trial activity representing the translation of research knowledge into interventions that influence 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 bibliometric 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 disease 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 disseminated to the research community through publications, translated into

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, multidisciplinary research approach to better understand basic mechanisms, etiology and risk factors, and to support the development of interventions to mitigate 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 coordinate autoimmune disease research are minimal. Information on autoimmune 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 concludes 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 disease, (3) an orientation toward innovation, (4) a focus on evaluating the autoimmune disease 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 literature, 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 ADCC has not developed a strategic research plan in this area 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 transformation that 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 independent, 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 successfully, 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, sustained, 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 opportunity not only for filling gaps that may fall between the work of diverse ICs, but also, as discussed in Chapter 4, capturing and leveraging an understanding 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 better 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, establishing 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

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 committee found that the best option for addressing these challenges and opportunities would be creating an office of autoimmune disease in the Office of the 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 stimulating innovation around autoimmune disease research;
• Engaging in priority setting, strategic planning, and implementation;
• Budgeting for and allocating available autoimmune disease research funds in alignment with the strategic plan;
• Managing and evaluating autoimmune disease 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 opportunities, 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 concern (e.g., National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, and National Institute of Arthritis and Musculoskeletal and Skin Diseases) or increasing funding to ICs that 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 common fund or direction to certain focused activities. Funding for an “autoimmune 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

TABLE 7-1 Options for Enhancing NIH Autoimmune Disease Research

in biomedical research that no single NIH IC can address on its own. Other options would be to model focused autoimmune disease research activities after other cross-NIH activities such as the All of Us Research Program,¹ an effort that seeks to advance individualized health care by enrolling 1 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 neurotechnologies.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), Accelerating Medicines Partnership^® (AMP^®) Program including Autoimmune and Immune-Mediated Diseases (AMP^® AIM), and the Immune Tolerance Network (Chapter 5) are examples of such focused research activities. Funding to further strengthen the autoimmune disease research

___________________

¹ Available at https://allofus.nih.gov/about/faq (accessed February 25, 2022).

² Available at https://braininitiative.nih.gov/sites/default/files/pdfs/brain_technical_one_pager_1072022_508c.pdf.

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 administrative burden since they would leverage existing mechanisms. Disadvantages 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 opposition 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 considerations, 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 the 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 disease research (2005). The committee 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, autoimmune 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

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 placement within NIAID. The 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 divisions. 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 Secretary. 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. Agencies such as the Agency for Healthcare Research and Quality (AHRQ), Centers for Disease Control and Prevention (CDC), Centers for Medicare & Medicaid Services (CMS), Health Resources and Services Administration (HRSA), Substance Abuse and Mental Health Services Administration (SAMHSA), as well as the Administration on Aging and the Indian Health Service would have specific expertise in these areas. CDC could provide perspectives on public health dimensions of autoimmune disease. CMS and HRSA could provide expertise on health care issues, and the Food and Drug Administration could advise 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

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 policymaking 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 disengaged response. Discussion can lack depth, nuance, or perceived immediate 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 Disease/Autoimmunity Research Plan

The committee considered and believes that there may be significant value in a congressionally mandated National Autoimmune Disease/Autoimmunity Research Plan that could be sited in any one of a number of organizational entities. There is useful precedent for such a plan, perhaps most notably the National Plan to Address Alzheimer’s Disease (AIM, 2021). NIH is an active participant in providing input to and implementing 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 milestones 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.

of individuals affected. For example, the estimated number of affected individuals living with Alzheimer’s disease is 5.1 million (HHS, 2020), compared with 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 assembling 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 process would involve consulting with internal and independent experts from diverse fields, providing substantial opportunities for public engagement and input, providing regular detailed updates on progress, and convening one or more summits. 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 funding, overseeing, and otherwise taking a special interest in NIH autoimmune 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 researchers to propose, examine, and receive funding for new lines of research. 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 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 expectations unreasonably, and focusing on predetermined goals and objectives might cause leaders and researchers to be less attentive to complementary 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 systems 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 information 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 programs, 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 Institute is by definition administratively daunting and would require congressional action. Creating a new Institute would also require a long-term view and patience, neither of which may hold appeal to those

anxious for progress. Thus, creating a new Institute 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 confusion during an initial period of transition.

While reorganizations can bring key people together “under one roof,” they inevitably dislocate key people as well. Moreover, creating new units could engender resistance and resentment from existing entities, neither of which advances the research enterprise. Finally, creating a new Institute risks unrealistically raising expectations about focus, resources, and research outcomes.

Option 5: Create an Office of Autoimmune Disease/Autoimmunity Research within the Office of the Director of NIH

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 supporting autoimmune disease research, promote the appropriate allocation of NIH for autoimmune disease research, report on research activities and identify future research opportunities, and provide leadership on autoimmune disease to HHS, the NIH Director and other relevant agencies.

As governmental units at NIH and elsewhere persuasively argue to Congress, the impact of a research organization is likely to correlate with the extent to which it owns and controls resources. This is particularly true in the case of new entities advising on and negotiating 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 control certain key budgetary decisions about autoimmune disease research activities conducted elsewhere in NIH, the Office of AIDS Research (OAR) 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 committee 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.

Success will also depend on tailoring OAD/AR to specific and manageable 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 suggest 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 OD. Based on these reviews, the Committee concludes that OAR can provide a highly desirable model for a new Office of Autoimmune Disease/Autoimmunity Research. This organizational model has provided 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 a strategic plan for HIV and HIV-related research throughout NIH;
• Assurance that funds are invested in the areas of scientific priority and such funding is allocated;
• Oversight, coordination, and management of HIV and HIV-related research (scientific, budgetary, legislative, and policy) in collaboration with other NIH entities (ICs participate in Office advisory bodies);
• Convening stakeholders, encouraging collaboration and catalyzing innovation to address emerging scientific and public health challenges; and
• Including attention to workforce development in strategic goals for HIV and HIV-related research.

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/COVID19 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 pandemic and considered mitigation strategies to assure that the conduct of HIV research would not be negatively affected by the COVID-19 experience. 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 prevention 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 OAR as a model, the committee believes that a well-configured OAD/AR could be an essential ingredient in further stimulating promising and impactful autoimmune disease and autoimmunity research at NIH that can be translated into clinical practices that will prevent autoimmune disease or improve the lives of those living with autoimmune disease.

The Committee envisions the following responsibilities for the Office:

1. 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 opportunities that align with strategic plan goals (e.g., developing solicited requests for applications (RFAs) for crosscutting research grants, promoting Small Business Innovation Research (SBIR)

and Small Business 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 breakthroughs 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 vocabulary that includes both clinically defined autoimmune diseases and autoimmune mechanisms and a list of autoimmune diseases. Such a definition and list of diseases is critical to improve research and data collection and to guide patient care and coordinate communication. Periodic reassessment of the definition and listing of autoimmune diseases, should be undertaken based upon emerging data.

2. 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 autoimmune disease research activities including those that are crosscutting, high risk/reward, relevant to special populations, and related to workforce development.
3. The Office would provide scientific coordination and management of the research program. This would include:
   1. Serving as a focal point for external parties seeking information or providing input on autoimmune disease research opportunities at NIH.
   2. Serving as a convener for emerging and crosscutting science on autoimmune disease. Collaborating with organizations

focused on persons-centered research, such as the 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 multiple 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, animal, translational) and human studies, and evaluate assignment 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 collaboration, 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.
4. The Office would conduct or contract for evaluations of ongoing efforts.
5. The Office would produce annual reports on the progress made on autoimmune disease research activities for 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 autoimmune disease research enterprise and members of the public.
6. Building on this report and other relevant reviews, the Office would lead the development of an enhanced information system 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 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 Institute 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, intramural, 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 Offices in the NIH OD 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, measurement, and evaluation.

OAD/AR would independently advocate for and promote transparency, and it would establish a framework for accountability among relevant ICs. 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 autoimmune 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 potential 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.

RECOMMENDATIONS

As discussed above, 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, establishing a new Institute, and creating a special office for autoimmune disease research. With the caveats noted above, the committee believes that a well-configured Office of Autoimmune Disease/Autoimmunity Research could be an essential ingredient in further stimulating promising and impactful autoimmune disease and autoimmunity research at NIH that can be translated into clinical practices that will prevent autoimmune diseases or improve the lives of those living with autoimmune disease.

Acknowledging that creating an OAD/AR may take some time, the committee makes two specific recommendations related to data collection that could be implemented 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 epidemiology on the individual and aggregate burden of autoimmune disease. The extant knowledge base is growing, but there are important gaps, including incidence and prevalence trends, comprehensive evaluations of the risk factors and the burden (including direct and indirect costs) of these diseases, the impact on different populations, the trajectory of these diseases from the period before disease manifests through the life course, and the impact of specific treatments and interventions.

The committee found a lack of long-term (20 years or more) population-based epidemiology studies on autoimmune disease. Such studies would allow for assessing trends, identifying differences among population subgroups, and 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 that already exists at NIH.

The committee also found that few studies exist that are able to provide information on the long-term progression of autoimmune disease beginning in the period before disease manifests through the life course. Such studies would allow for a greater understanding of the heterogeneity of disease expression and changes with time and over various life stages. Such studies could be designed to address a 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 morbidities change over time. It is essential to support long-term (10–20+ years) patient cohort studies. Such studies would provide understanding of opportunities for developing clinical treatments and behavioral interventions.

Finally, to address the research gaps outlined throughout this report, a comprehensive national research agenda for autoimmune diseases is required. Achieving this objective will require coordination and

collaboration among researchers, research groups, and stakeholders as well as the dedicated pursuit of research that defines autoantibodies that predict and diagnose autoimmune diseases; identifies common mechanisms in inflammation; determines gene–environment interactions within and across autoimmune diseases; examines the role of environmental exposures on autoimmune diseases; elucidates disparities and their determinants; determines the impact of coexisting morbidities and complications of autoimmune diseases on clinical outcomes, functional outcomes, quality of life, and health care utilization; and explores the effect of interventions 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 comprehensive national research agenda that incorporates the thinking of associated ICs and other stakeholders, and as such illustrates the role that an OAD/AR could fill as no other currently existing entity could.

Heterogeneity in autoimmune diseases takes many forms, which could range from differences in symptom presentation and disease progression, as seen in persons with systemic lupus erythematosus, to severity of disease, as observed in myocarditis in men compared with women, to varying responses to the same therapy.

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 hormones, 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.

Chapter 4 reviewed a variety of signals being explored as biomarkers to predict disease, confirm diagnosis, and predict flares of disease.

Further investigation of these and novel signals can inform preventive and therapeutic strategies.

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.

pathways that may predict response to treatment, and (3) inform understanding 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 therapies 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, 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.

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 developing interventions to prevent or ameliorate these could greatly improve patient care.

There are disparities in who develops autoimmune diseases as well as how the diseases progress; among the causes for disparities are differences in living environments, access to and affordability of care, and even provision of care. Researchers have observed, for example, that Hispanic

patients and patients in the U.S. South with autoimmune disease-related kidney failure are less likely to receive kidney transplants than non-Hispanic 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.

Chapter 2 noted that 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. As these costs will impact public health budgets, research to define costs should be undertaken as findings could inform research priorities.

REFERENCES

This page intentionally left blank.