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Suggested Citation:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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:"Summary." 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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Summary1 Autoimmune diseases occur when the body’s immune system, which normally defends the body against disease and infection, malfunctions and mistakenly attacks healthy cells, tissues, and organs. Common auto- immune diseases include celiac disease, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, and type 1 diabetes. Auto- immune diseases are chronic, lifelong, and can cause significant physical and psychosocial impairment, impeding activities of daily living, produc- tivity, and quality of life. They can occur at any age, and many but not all, predominantly affect women, with female to male ratios reaching 6:1 or higher for some diseases. Autoimmune diseases as a group rank among the ten leading causes of death for females. Individuals with an autoim- mune disease commonly develop more than one autoimmune disease, and they can be at increased risk of developing cancer and cardiovascular disease as well as a wide variety of other illnesses and complications. There are no known cures for autoimmune diseases. There is no consensus on what illnesses are autoimmune diseases; counts range from over 80 to 150 diseases depending on the source. Defi- nitional boundaries of autoimmunity and autoimmune disease are evolv- ing, and there are differing approaches to characterizing autoimmune diseases—one based on clinical criteria and another based on underlying biological mechanisms. The diseases are heterogeneous in presentation, 1 References are not included in the report summary. Please view the body of the report for a full list of works cited. 1 PREPUBLICATION COPY—Uncorrected Proofs

2 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE and using stringent clinical criteria can impede the optimal design of clini- cal trials and studies as well as the diagnosis and care of patients. Strong epidemiologic data of the U.S. incidence and prevalence of autoimmune diseases in the last 10–20 years is limited, and a lack of population-based data is of particular concern. The last study that consid- ered autoimmune diseases as a whole in the United States was published in 2009 and estimated the prevalence of autoimmune diseases to be 7.6 to 9.4 percent—or 25 to 31 million people today.2 However, this estimate was based on only 29 autoimmune diseases, and it does not account for increases in prevalence in the last decade. The impact of autoimmune diseases is significant, and trend data are showing an increasing inci- dence and/or prevalence of most autoimmune diseases the committee examined, including in children, in whom an increased prevalence of IBD and type 1 diabetes were observed in the last decade. The earlier an autoimmune disease manifests, the longer an individual must live with accruing damage, increased risks of complications and other conditions, and adverse effects on quality of life. No single pattern of racial and ethnic disparities is seen in incidence or prevalence among autoimmune dis- eases; for some conditions, the highest rates occur among Black, American Indian, and Alaska Native populations, while for others, the highest rates occur in White populations. Disparities in the severity and prognosis of autoimmune diseases have been observed as well as disparities in the provision of care. There is little data on the direct and indirect costs in the United States of specific autoimmune diseases or of autoimmune diseases overall. However, one study found the annual direct costs of multiple sclerosis to be second only to congestive heart failure, and another esti- mated the average total lifetime cost for patients with Crohn’s disease, an inflammatory bowel disease, to be $622,056. Congressional interest in autoimmune diseases, driven largely by constituents, advocacy groups, and other stakeholders, is longstanding, and congressional requests and mandates have contributed to the trajectory of NIH autoimmune disease research. CHARGE TO THE COMMITTEE In response to a congressional request, the National Institutes of Health (NIH) asked the National Academies of Sciences, Engineering, and Medicine to form an expert committee to assess NIH research activities on 2 Based on 2020 U.S. Census of 331.4 million people. Available at: https://www.census. gov/library/stories/2021/08/united-states-adult-population-grew-faster-than-nations- total-population-from-2010-to-2020.html (accessed December 22, 2021). PREPUBLICATION COPY—Uncorrected Proofs

SUMMARY 3 autoimmune diseases with a particular emphasis on the risk factors, diag- nostic tools, barriers to diagnoses, treatments, and prospects for cures. The committee’s task also included considering the occurrence of multiple autoimmune diseases and the interplay of the diseases with comorbidi- ties, as well as identifying barriers to NIH-sponsored research, research gaps, and promising areas for future NIH-sponsored research that would benefit the greatest need. Box S-1 provides the committee’s Statement of Task. COMMITTEE’S APPROACH TO ADDRESSING ITS CHARGE The committee formed to address NIH’s task comprised 13 experts in autoimmune diseases, immunology, epidemiology, environmental health, BOX S-1 Statement of Task The National Academies of Sciences, Engineering, and Medicine will convene an ad hoc committee to conduct a congressionally mandated study of NIH re- search on autoimmune diseases. The study will: • Provide a general overview (with particular focus on NIH research efforts) of epidemiologic trends in autoimmune diseases. • For common autoimmune diseases (including those that are overrep- resented in women), evaluate the NIH research portfolio with particular attention to issues such as risk factors; diagnostic tools; barriers to diag- noses; treatments; and prospects for cures. • Review NIH’s research activities related to specific autoimmune diseas- es, the occurrence of multiple autoimmune diseases in individuals, and the interplay of autoimmune diseases and comorbidities. • Assess trends in the focus of NIH research and address whether the trends are reflective of the changes in epidemiology as compared to other factors such as availability of research tools and technologies, and emerg- ing biomedical knowledge and concepts. • Identify barriers to NIH-sponsored research and research gaps for autoim- mune diseases. • Identify promising areas for future NIH-sponsored research for autoim- mune diseases that would benefit the greatest need. • Evaluate Institute and Center structure in support of NIH autoimmune disease research to identify where needs are met and where coordination could be enhanced. • Produce  and  publish  a final consensus committee report summarizing the committee’s findings, conclusions, and recommendations. The report must address NIH accomplishments, challenges that NIH faces, as well as possible solutions to the challenges. PREPUBLICATION COPY—Uncorrected Proofs

4 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE neurology, nephrology, gastroenterology, cardiology, psychiatry, rheuma- tology, disability, pediatrics, women’s health, sex differences research, health disparities research, and research administration. The committee convened virtually ten times, including three public sessions to gather information from individuals with expertise on topics and subjects of interest to the committee, including panels of representatives of NIH institutes, centers, and offices; and experts on autoimmune diseases and autoimmune disease research from academia and disease-focused organizations. Given the study timeframe, the committee chose a select number of autoimmune diseases to examine as it would be unable to examine a large set of diseases. Initially the committee cross-referenced diseases that two autoimmune disease organizations3 agreed upon. To arrive at a final list, the committee considered autoimmune diseases that are identified in con- gressional language requesting this study; are overrepresented in women; may affect multiple systems and are associated with comorbidities; and that illustrate the spectrum of autoimmune disease. A final consideration was the availability of data on NIH research funding for the disease, as the committee had determined that this could provide valuable informa- tion on the focus of NIH’s autoimmune disease research portfolio. The committee selected 11 diseases for special focus: Sjögren’s dis- ease, systemic lupus erythematosus, antiphospholipid syndrome, rheu- matoid arthritis, psoriasis, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), celiac disease, primary biliary cholangitis, multiple sclerosis, type 1 diabetes, and autoimmune thyroid disease (Graves’ dis- ease and Hashimoto’s thyroiditis). The Study Process and Information Gathering The committee first undertook a high-level examination of the 11 select diseases that illustrate the spectrum of autoimmune diseases, inves- tigating each for epidemiology and impact, risk factors and etiology, diag- nostic tools, treatments and prospects for cures, heterogeneity in presenta- tion, animal models aiding in the understanding of the disease, as well as applicable research progress and gaps in answer to the statement of task. With this context, the committee determined that the characteristics that distinguish autoimmune diseases from each other are important and provide valuable information about the pathogenesis of each disease. 3 The Autoimmune Association is a non-profit organization focused on the impact of autoimmunity and the eradication of autoimmune diseases. The Autoimmune Registry, Inc., is a non-profit organization serving as a hub for research, statistics, and patient data on autoimmune diseases. PREPUBLICATION COPY—Uncorrected Proofs

SUMMARY 5 However, the committee also recognized, and chose to highlight and dis- cuss, the commonalities among autoimmune diseases. The committee then undertook a review of the NIH research portfolio on autoimmune disease. The general framework for this review included, to the extent possible, reviewing a set of inputs (spending), activities (research conducted) and outputs (clinical trials, patents and other indica- tors) of NIH’s investment in autoimmune disease research. The committee examined overall NIH spending for autoimmune dis- ease research grants and projects and that of 13 ICs that contribute the most funding to autoimmune disease research. The committee examined congressional action regarding NIH autoimmune disease research, the different types of NIH funded grants and awards, the process for review- ing and awarding grants, and the funding and operation of extramural and intramural programs. The committee also reviewed NIH-wide and individual-IC missions and strategic plans; autoimmune disease-related initiatives involving collaboration; and NIH approaches to coordinating research. To examine the activities of the NIH-funded autoimmune disease research portfolio, the committee relied on two sources: NIH’s Research, Condition, and Disease Categorization system (RCDC) and the NIH Research Portfolio Online Reporting Tools (RePORT) website. The com- mittee analyzed data from fiscal year 2008, the first year for which data were available through fiscal year 2020, the last year for which data were available at the time of analysis. All grants/projects categorized as being in the RCDC “autoimmune diseases” spending category for the desig- nated period were assembled, and the resulting 8,470 grants constituted the committee’s research database. The committee determined that cer- tain types of grants merited particular attention in portfolio evaluation; investigator-initiated (R) grants, for example, are the bulk of NIH-funded research. The specified award types were analyzed by the committee in a variety of ways and according to NIH overall, individual ICs, and each disease of interest. The statement of task directed the committee to evaluate the NIH research portfolio for issues such as risk factors, diagnostic tools, barri- ers to diagnoses, treatments, and prospects for cures. As reviewing 8,470 abstracts individually was not deemed feasible, the committee chose three approaches to the task, and the methodologies for these appear in Chap- ter 6 and Appendix H. The first applied topic modeling to identify the most common grant research topics and the fluctuation in these topics over time. For the second approach, the committee searched the abstract database to identify which other NIH RCDC spending categories co- occurred with the autoimmune disease-spending category; this analysis provided insight into themes in autoimmune disease research. For the PREPUBLICATION COPY—Uncorrected Proofs

6 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE third method, committee members used their scientific knowledge and expertise to review a sample of over 1,200 abstracts to assess the primary areas of research focus as identified in the statement of task. The committee’s approach to assessing the accomplishments, or out- puts, of funded research on autoimmune disease included a high-level examination of clinical trial activity, bibliometric indicators, and patents. The methodologies are in Appendix G. CROSSCUTTING ISSUES IN AUTOIMMUNE DISEASES Based on its review of the literature, the committee highlighted the characteristics that are common across autoimmune diseases because they provide valuable information about disease pathogenesis that could provide direction for more targeted research that might lead to strategies to prevent, delay, diagnose, treat, and cure disease. Considering autoim- mune diseases as a “group” according to “common mechanisms of dis- ease” might provide novel insights beyond those gained by focusing on the affected organ or system, or on individual diseases. Below are areas of research opportunity. Genetics. Autoimmunity appears to require interaction between envi- ronmental factors and one or more genes. Many of the genes that confer susceptibility to autoimmune disease, and that the diseases share, regu- late immune response; dysfunction of the immune response is critical to the development of autoimmune disease. Identifying the mechanisms that underlie genotype–phenotype associations will enable researchers to better target treatment. Environmental exposures. Research supports a “second-hit” hypothesis— that a genetic profile requires an additional exposure event to become clinical illness. Among the exposures associated with autoimmune dis- eases are infectious agents and respirable silica. Defining the type and duration of exposures associated with disease for specific diseases and across diseases, as well as defining the permutations of genes and envi- ronmental exposures that lead to autoimmune diseases could benefit the field. Biomarkers. Biomarkers such as cytokines and autoantibodies can be detected before clinical disease develops and an increase in pro-inflam- matory cells, cytokines, and signaling pathways are implicated in disease development. Identifying traditional and novel biomarkers could enable disease prediction, which coupled with advances in therapeutic areas could possibly be used to delay or prevent disease before clinical disease develops, or modify disease outcomes. Sex. Sex chromosomes, sex hormones, and the effects of environ- mental exposures on sex hormones appear to play a role in differences PREPUBLICATION COPY—Uncorrected Proofs

SUMMARY 7 between males and females in the occurrence and pathogenesis of autoim- mune disease. Understanding this activity better could inform approaches to diagnosis and treatment. Autoimmune disease complications / coexisting autoimmune diseases. Both are common, with some illnesses occurring across several autoimmune diseases. Examining the patterns could inform the understanding of pathophysiology and mechanistic pathways as well as approaches to patient care. Mechanistic pathways as therapeutic targets. Mechanisms of immune- mediated damage that leads to the varied clinical phenotypes of different diseases may share common immune pathways. Identification of specific proinflammatory signaling pathways and their cytokines as pathogenic in autoimmune diseases has resulted in targeted therapeutics; some thera- pies have been shared across diseases. Discovery of further pathways that promote or inhibit autoimmune disease could inform drug development. Animal models. Existing animal models have and can continue to help define common genetic and environmentally induced mechanisms. Development of models for diseases that do not have models and contin- ued development of a variety of novel culture, animal, and other models to better answer questions posed by advances in translational research would benefit the field of autoimmune disease. ANALYSIS OF INSTITUTE AND SPECIFIC AUTOIMMUNE DISEASE RESEARCH ACTIVITY In reviewing NIH’s research portfolio on autoimmune diseases, the committee employed a general framework that considered the inputs (spending), activities (research conducted) and outputs (clinical trials, patents and other indicators) of NIH’s investment in autoimmune disease research. It is notable that spending on autoimmune diseases as a percent of overall NIH obligations has remained at only 2.6 percent between 2013 and 2020. This is in marked contrast to increases seen in overall NIH obligations during the same period. In addition, the distribution of this funding for autoimmune diseases indicates that certain ICs dominate overall spending on research and training and the types of research activi- ties funded. An overview of the focus of the funded autoimmune research grants as requested by the statement of task was conducted using three dif- ferent methodologies—artificial intelligence, NIH RCDC spending cat- egories, and committee member judgement—yielding different levels of specificity. While there was some consistency in the focus areas identified among the three methods—the areas of pathophysiology of the immune PREPUBLICATION COPY—Uncorrected Proofs

8 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE response, genetics, and treatment and therapy were common to all three methods—some methods highlighted other areas of focus more readily. For accomplishments associated with funded research on autoim- mune disease, the committee considered clinical trial activity, which rep- resents translating research knowledge into interventions that influence health-related biomedical or behavioral outcomes; bibliometric indicators; and patents. With respect to clinical trials, there is a greater percentage of clinical trials from filing years 2008 to 2020 for such autoimmune diseases as type 1 diabetes, systemic lupus erythematosus, IBD and rheumatoid arthritis, with a much smaller percentage seen for other autoimmune diseases. Further, results from bibliometric analyses indicate that the knowledge associated with existing research grants has been success- fully disseminated to the research community through publications in well-regarded scientific journals. In terms of patent applications, filings occur primarily for some autoimmune diseases with far fewer filings for others. In general, findings related to research outputs suggest the need for a nuanced and in-depth examination of why progress via clinical trials and patent filings does not seem to have been made for certain autoim- mune diseases. Despite the generation of important information summarizing the autoimmune disease research enterprise, the committee encountered substantial challenges in making quantitative or qualitative judgements about the portfolio and the progress made to address the broad range of autoimmune diseases. In part, this is because a recent overarching stra- tegic research plan with implementation goals and milestones does not exist, thus the committee was unable to discern concrete metrics against which progress could be assessed. OPPORTUNITIES AND OPTIONS FOR ENHANCING AUTOIMMUNE DISEASE RESEARCH AT NIH The committee’s formal 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 also faced a daunting task given the evolving areas of autoim- munity and autoimmune disease, differing approaches to defining auto- immune disease, lack of consensus on what diseases they include, and a lack of epidemiologic data. The examination of the 11 diseases highlights the complexity of autoimmune diseases ranging from molecular mecha- nisms to individuals, families and populations affected, heterogeneity in presentation and evolution of the disease, and in available treatments and the responses to therapy. The committee agreed that the diseases’ commonalities may provide additional and significant insights that can PREPUBLICATION COPY—Uncorrected Proofs

SUMMARY 9 further the development of patient care and therapies, and as such may offer the greatest opportunity for advancing the field. The general framework for the review of the NIH autoimmune dis- ease research portfolio includes inputs (funding, organizational structure and administrative processes, IC missions and strategies, collaborative initiatives, and methods of collaboration), activities (the kinds of research funded), and outputs or accomplishments. Major barriers to NIH’s ability to maximize outcomes of this research portfolio is the variation found in IC strategic plans regarding autoim- mune diseases and most significantly, the absence of a research plan that spans all ICs to provide an overall strategic NIH plan for autoimmune diseases. Absent the latter, NIH lacks a comprehensive, transparent, and strategic approach to how it plans and evaluates progress made on auto- immune disease research. The committee determined that five essential elements are neces- sary for rapid advancement and improvement in autoimmune disease research: 1. Strategic research planning to set priorities 2. An emphasis on coordinating across ICs and enhancing collab- orative research given the crosscutting nature of autoimmune diseases 3. An orientation toward innovation 4. A focus on evaluating the autoimmune research portfolio in order to determine progress made across NIH 5. Resources to support planning, collaboration, and innovation 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, NIH does not optimally promote these five elements. Identifying gaps and opportunities can be achieved by a relatively independent, structured, and ongoing examination of the research con- ducted. This can then inform planning for how to most successfully address those gaps and opportunities, which would also benefit from a detailed but not prescriptive strategic plan. Neither a rigorous evalua- tion nor strategic planning currently occurs in an overarching, sustained, and resourced fashion. There currently is no overarching strategic plan guiding research activities and IC collaboration on autoimmune research activities. The committee identified an opportunity not just for filling gaps that may fall between the work of diverse ICs but also for capturing and leveraging an understanding of the crosscutting nature of autoimmune PREPUBLICATION COPY—Uncorrected Proofs

10 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE diseases, including their underlying common disease mechanisms, risk factors, and shared concomitant conditions. The committee believes that the emerging and evolving science now makes those connections more achievable than ever before. Such information could be building blocks for, and could accelerate innovative progress toward prevention, early diagnosis, 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 the 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. These included (1) Increased funding for autoimmune disease research; (2a) coordination through revi- talization of the NIH Autoimmune Disease Coordinating Committee; (2b) coordination through creation of a U.S. Department of Health and Human Services Autoimmune Disease Coordinating Committee; (3) development of a congressionally mandated national autoimmune diseases/autoim- munity research plan; (4) creation of a new National Institute of Autoim- mune Disease and Autoimmunity Research; and (5) creation of an Office of Autoimmune Disease/Autoimmunity Research within the Office of the NIH Director. The pros and cons, costs, and feasibility of each option are discussed in Chapter 7. The committee found that the best option for addressing these chal- lenges and opportunities would be the creation of an Office of Autoim- mune Disease/Autoimmunity Research within the Office of the NIH Director. It found significant merit in this option, provided the option is pursued in a way in which it is likely to succeed. 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 implementation • Budgeting for and allocating available research funds in align- ment with the strategic plan • Managing and evaluating research efforts • Communicating with key stakeholders • Providing visible leadership on autoimmune disease research. This option is not a new one and was proposed in a bill advanced by then Senator Joe Biden in 1999. Realistically, as governmental units at NIH and elsewhere persua- sively argue to the Congress, the impact of a research organization is PREPUBLICATION COPY—Uncorrected Proofs

SUMMARY 11 likely to be correlated with the extent to which it owns and controls resources. This is particularly true in the case of new entities negotiat- ing and advising over the activities of multiple actors who are already resourced. Given this, the committee considered two configurations of this Office. In the first, the Office would have its own research budget and it would substantially control certain key budgetary decisions about auto- immune disease research activities conducted elsewhere in NIH. 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. Current offices have budgets that range widely, which can affect an office’s ability to fund research, and most offices are permitted to fund grants only in collaboration with an IC. The ability of the Office of AIDS Research to allocate congressionally appropriated funds for AIDS research is unusual. The committee recommends the former, fully recognizing that budgetary control is among the most sensitive issues within any organi- zation. The committee recognizes that some middle ground might need to be struck. Success will also depend on tailoring the Office to specific and man- ageable objectives. Further, a successful crosscutting office needs the capacity to suggest and advance creative new scientific approaches, part- ners, 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 pursue. This, in the view of the committee, is how a new Office of Autoimmune Disease/Autoim- munity Research within the Office of the NIH Director would provide its greatest value. As noted above, the committee believes that successful implementa- tion of any option will depend on careful attention of a variety of criti- cal success factors in addition to budget considerations. Simply put, the committee believes that no new Office is preferable to one that is not sub- stantive, serious, supported, well defined and well resourced. 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 at NIH that does not meet those standards. With these provisos, the committee believes that a well-configured Office of Autoimmune Disease/Autoimmunity Research could be an essential ingredient in further stimulating promising and impactful auto- immune disease and autoimmunity research at NIH that can be trans- lated into clinical practices that will prevent autoimmune diseases from occurring or that will improve the lives of those living with autoimmune disease. The responsibilities the committee envisions for the Office appear in Box S-2. PREPUBLICATION COPY—Uncorrected Proofs

12 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE BOX S-2 Duties of the Office as Envisioned by Committee 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 cross- cutting 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 Inno- vation Research (SBIR) and Small Business Technology Transfer (STTR) Programs grants). 5. Address autoimmune disease research workforce and training issues, includ- ing 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 clini- cally 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 guide patient care and coordinate communica- tion. Periodic reassessment of the definition and listing of autoimmune diseases, should be undertaken based upon emerging 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 cross- cutting; high risk/reward; relevant to special populations; and related to work- force development. PREPUBLICATION COPY—Uncorrected Proofs

SUMMARY 13 C. 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 autoim- mune disease. Collaborating with organizations focused on persons-centered research like the Patient-Centered Outcomes Research Institute and other stakeholders—industry, disease organizations, patient advocacy, and pa- tients 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 ap- propriate 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 bio- repository 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 ef- forts 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 autoimmune research enterprise and members of the public. F. Building on this report and other relevant reviews, the Office would lead the de- velopment of an enhanced information system for autoimmune disease research. The committee’s efforts revealed challenges researchers and policy-makers may face in easily accessing, synthesizing and analyzing relevant research opportuni- ties 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. PREPUBLICATION COPY—Uncorrected Proofs

14 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE The committee’s recommendations follow, the introduction for Rec- ommendation 1 having been provided. 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. 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 PREPUBLICATION COPY—Uncorrected Proofs

SUMMARY 15 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 indi- vidual patient level. Autoimmune diseases are long-lasting e heteroge- neous conditions for which manifestations and comorbidities 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. 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 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 deter- minants; determines the impact of comorbidities 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 comorbidities and complications for patients with autoimmune disease across the lifespan. PREPUBLICATION COPY—Uncorrected Proofs

16 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE 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. • Dissect heterogeneity across and within autoimmune diseases to decipher common and disease-specific pathogenic mechanisms • Study rare autoimmune diseases and develop supporting animal models • Define autoantibodies and other biomarkers that can diagnose and predict the initiation and progression of autoimmune diseases • Determine the biologic functions of genetic variants and gene– environment interactions within and across autoimmune diseases using novel, cutting-edge technologies • Examine the role of environmental exposures and social determi- nants of health in autoimmune diseases across the lifespan • Determine the impact of coexisting morbidities, including co- occurring autoimmune diseases and complications of autoim- mune diseases, across the lifespan, and develop and evaluate interventions to improve patient outcomes. • Foster research to advance health equity for all autoimmune dis- ease patients The committee provides detailed subheadings for these research areas in Chapter 7. CONCLUSION The quantity and quality of the research NIH conducts on autoim- mune diseases is impressive. The committee believes that a strategic plan for all NIH autoimmune disease research and a well-configured and well- funded Office to support the coordination and collaboration of all ICs that can play a role in advancing the field represent an opportunity for NIH to both optimize its significant resources and to maximize the ground covered by the research it conducts. 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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