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 autoimmune diseases include celiac disease, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease (IBD), and type 1 diabetes. Autoimmune diseases are chronic and lifelong and can cause significant physical and psychosocial impairment, impeding activities of daily living, productivity, 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 10 leading causes of death for females. Individuals with an autoimmune 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 more than 80 to 150 diseases depending on the source. Definitional boundaries of autoimmunity and autoimmune disease are evolving, 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
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1 References are not included in the report summary. Please view the body of the report for a full list of works cited.
presentation, and using stringent clinical criteria can impede the optimal design of clinical 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 past 10–20 years are limited, and a lack of population-based data is of particular concern. The last study that considered 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 past decade. The impact of autoimmune diseases is significant, and trend data are showing an increasing incidence and/or prevalence of most autoimmune diseases the committee examined, including in children, in whom an increased prevalence of inflammatory bowel disease (IBD) and type 1 diabetes were observed in the past 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 diseases; 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 estimated the average total lifetime cost for patients with Crohn’s disease, an IBD, 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 National Institutes of Health (NIH) autoimmune disease research.
CHARGE TO THE COMMITTEE
In response to a congressional request, NIH asked the National Academies of Sciences, Engineering, and Medicine to form an expert committee
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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).
to assess NIH research activities on autoimmune diseases with a particular emphasis on the risk factors, diagnostic tools, barriers to diagnoses, treatments, and prospects for cures. The committee’s task also included considering the occurrence of multiple autoimmune diseases in individuals and the interplay of the diseases with comorbidities, as well as identifying barriers to NIH-sponsored research, research gaps, and promising areas for future NIH-sponsored research that would benefit the greatest need. Box S-1 provides the committee’s Statement of Task.
COMMITTEE’S APPROACH TO ADDRESSING ITS CHARGE
The committee formed to address NIH’s task consisted of 13 experts in autoimmune diseases, immunology, epidemiology, environmental
health, neurology, nephrology, gastroenterology, cardiology, psychiatry, rheumatology, disability, pediatrics, women’s health, sex differences research, health disparities research, and research administration. The committee convened virtually 10 times, including 3 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 and Centers (ICs) 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 congressional language requesting this study; are overrepresented in women; may affect multiple systems and are associated with comorbidities; and that illustrate the spectrum of autoimmune diseases. 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 information on the focus of NIH’s autoimmune disease research portfolio.
The committee selected 11 diseases for special focus: Sjögren’s disease, systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid 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’ disease 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, investigating each for epidemiology and impact, risk factors and etiology, diagnostic tools, treatments and prospects for cures, heterogeneity in presentation, 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.
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3 The Autoimmune Association is a nonprofit organization focused on the impact of autoimmunity and the eradication of autoimmune diseases. The Autoimmune Registry, Inc., is a nonprofit organization serving as a hub for research, statistics, and patient data on autoimmune diseases.
However, the committee also recognized, and chose to highlight and discuss, 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 indicators) of NIH’s investment in autoimmune disease research.
The committee examined overall NIH spending for autoimmune disease 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 reviewing 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 committee 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 designated period were assembled, and the resulting 8,470 grants constituted the committee’s research database. The committee determined that certain 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, barriers 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 Chapter 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
third method, committee members used their scientific knowledge and expertise to review a sample of more than 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 outputs, 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 autoimmune diseases as a “group” according to “common mechanisms of disease” 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 environmental factors and one or more genes. Many of the genes that confer susceptibility to autoimmune disease, and that the diseases share, regulate 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 diseases 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 environmental 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-inflammatory 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 environmental exposures on sex hormones appear to play a role in differences
between males and females in the occurrence and pathogenesis of autoimmune 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 therapies 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 continued 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 CENTER 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 percentage 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 activities funded.
An overview of the focus of the funded autoimmune research grants as requested by the statement of task was conducted using three different methodologies—artificial intelligence, NIH RCDC spending categories, 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
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 autoimmune disease, the committee considered clinical trial activity, which represents 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 successfully 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 autoimmune 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 strategic 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 autoimmunity and autoimmune disease, differing approaches to defining autoimmune 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 mechanisms to individuals, families and populations affected, heterogeneity in presentation and evolution of the disease, and available treatments and responses to therapy. The committee agreed that the diseases’ commonalities may provide additional and significant insights that can 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 disease 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 autoimmune 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 autoimmune disease research.
The committee determined that five essential elements are necessary for rapid advancement and improvement in autoimmune disease research:
- Strategic research planning to set priorities
- An emphasis on coordinating across ICs and enhancing collaborative research given the crosscutting nature of autoimmune diseases
- An orientation toward innovation
- A focus on evaluating the autoimmune research portfolio in order to determine progress made across NIH
- 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 conducted. 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 evaluation 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
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 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. These included (1) increased funding for autoimmune disease research; (2a) coordination through revitalization 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/autoimmunity research plan; (4) creation of a new National Institute of Autoimmune Disease and Autoimmunity Research; and (5) creation of an Office of Autoimmune Disease/Autoimmunity Research within the Office of the Director of NIH. 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 challenges and opportunities would be the creation of an Office of Autoimmune Disease/Autoimmunity Research within the Office of the Director of NIH. 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 stimulating innovation around autoimmune disease research
- Engaging in priority setting, strategic planning, and implementation
- Budgeting for and allocating available research funds in alignment 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 persuasively argue to the Congress, the impact of a research organization is likely
to be correlated 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 of this Office.
In the first, the Office would have its own research budget and it would substantially control certain key budgetary decisions about autoimmune 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 organization. The committee recognizes that some middle ground might need to be struck.
Success will also depend on tailoring the Office to specific and manageable objectives. Further, 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 pursue. This, in the view of the committee, is how a new Office of Autoimmune Disease/Autoimmunity Research within the Office of the NIH Director would provide its greatest value.
As noted above, the committee believes that successful implementation of any option will depend on careful attention to a variety of critical success factors in addition to budget considerations. Simply put, the committee believes that no new office is preferable to one that is not substantive, 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 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 responsibilities the committee envisions for the Office appear in Box S-2.
The committee’s recommendations follow, the introduction for Recommendation 1 having been provided.
Recommendation 1: The Director of the National Institutes of Health should create an Office of Autoimmune Disease/Autoimmunity Research within the Office of the Director.
Acknowledging that creating an Office of Autoimmune Disease/Autoimmunity Research 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 already existing at NIH.
Recommendation 2: The National Institutes of Health should establish long-term systems to collect and ensure optimum usability of population-based surveillance and epidemiological data (e.g., incidence, prevalence) on autoimmune diseases and measures of autoimmunity (e.g., autoantibodies, 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 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 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 heterogeneous 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 National Institutes of Health 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 progression, coexisting morbidities, and long-term (20+ years) outcomes 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 treatment (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 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 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.
Recommendation 4: The National Institutes of Health 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 determinants of health in autoimmune diseases across the lifespan
- Determine the impact of coexisting morbidities, including co-occurring autoimmune diseases and complications of autoimmune diseases, across the lifespan, and develop and evaluate interventions to improve patient outcomes.
- Foster research to advance health equity for all autoimmune disease patients
The committee provides detailed subheadings for these research areas in Chapter 7.
CONCLUSION
The quantity and quality of the research NIH conducts on autoimmune 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 both to optimize its significant resources and to maximize the ground covered by the research it conducts.
