Arthritis & Rheumatology ( IF 13.3 ) Pub Date : 2024-02-25 , DOI: 10.1002/art.42837 Victoria K. Shanmugam 1 , Janine A. Clayton 1
Introduction
Although the exact prevalence of autoimmune diseases is unknown, estimates suggest they affect 7% to 8% of the US population.1-3 Mortality data for autoimmune diseases as a whole are incomplete due to challenges in reporting. However, a study from 2000 evaluated combined mortality data from 24 autoimmune diseases and demonstrated that, taken together, death from these conditions would rank autoimmune diseases as one of the leading causes of death for women.4 Reports also suggest an increasing incidence of autoimmunity over time.5 A recent population-based cohort study of 22 million individuals in the United Kingdom found a new diagnosis of 1 of the most common 19 autoimmune diseases occurring in 4.45% of individuals over an almost 20-year period. Of those individuals, 63.9% were female,6 and together, the 19 autoimmune disorders examined affected 10.2% of the population. In this study, rates of many of the autoimmune diseases demonstrated increased prevalence over time. The presence of co-occurring autoimmune diseases was also recapitulated in this study and has been shown by others,7 lending further evidence to potential shared etiologies or pathogenesis.
Large epidemiologic studies have for some time raised concerns regarding how to evaluate environmental exposures in autoimmune disease research. An expert panel convened in 2010 reported multiple environmental exposures associated with autoimmune diseases including crystalline silica, solvent and other chemical exposure, smoking, and radiation.1 However, studying environmental exposures in autoimmune disease research remains challenging due to complexities in understanding exposure latency, dose, and the interplay of exposures across the lifespan.
In 2022, the National Academies of Sciences, Engineering, and Medicine (NASEM) conducted an analysis examining research efforts of the National Institutes of Health (NIH) related to autoimmune diseases, publishing their findings in a report titled “Enhancing NIH Research on Autoimmune Diseases.”8 Based in part on the findings articulated in this report, Congress, via the Joint Explanatory Statement accompanying the Fiscal Year 2023 Consolidated Appropriations Act, subsequently directed the establishment of the Office of Autoimmune Disease Research (OADR) within the Office of Research on Women's Health (ORWH). With this, Congress additionally appropriated 10 million dollars of funding for the new OADR in 2023. Reliable sustained funding for autoimmune disease research will be needed to support the breadth and depth of research necessary to advance the study of autoimmune diseases.
The female predominance of many autoimmune diseases is well known9; although recent studies suggest Xist may play a role in sex differences in autoimmune diseases,10 the complexity of the female preponderance of autoimmune disease is not well understood. Understanding sex differences in biologic systems, particularly in health and disease, is a major focus of work supported by the ORWH.11, 12 In autoimmune diseases, changes in disease activity across the lifespan are well recognized and have historically been attributed to hormonal changes. However, it is increasingly recognized that immune responses differ in women and men at a cellular level, independent of changes in hormonal milieux, and the mechanistic underpinnings of those differences will be crucial to further understanding of the female preponderance of autoimmune disease.13, 14 Situating the OADR within the ORWH in the Office of the Director of the NIH will uniquely support its role in addressing autoimmune diseases across the lifespan and their impact on both men and women.
The funding strategy for the inaugural year of the OADR funding was based on recommendations from the NIH institutes, centers, and offices (ICOs) and included diseases considered to be within the autoimmune portfolio listed in the NASEM report.8 In fiscal year 2023, the OADR supported a total of 41 awards across 12 individual ICOs. These included 15 extramural cofunding awards, 3 R56 bridge funding awards, 2 Accelerating Medicines Partnership Autoimmune and Immune-Mediated Diseases awards, 10 intramural cofunding awards, 5 intramural scientific fellowships, and 6 Exposome in Autoimmune Disease Collaborating Teams Planning (EXACT-PLAN) awards. The EXACT-PLAN program (NOT-OD-23-112) was developed in partnership with the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Environmental Health Sciences along with ICO collaborators and focused on supporting the design, development, and implementation of a future national, interdisciplinary, collaborative team science research network that will advance the study of the exposome in autoimmune disease. The funded awards spanned basic to translational science, clinical, and public health research focused on autoimmune disease (Figure 1).
In establishing the OADR, Congress further directed the office to coordinate the development of a multi-institute and center strategic research plan (henceforth referred to as an NIH-wide Strategic Plan for Autoimmune Disease Research); identify emerging areas of innovation and research opportunity; coordinate and foster collaborative research across institutes and centers; annually evaluate the NIH autoimmune disease research portfolio; provide resources to support planning, collaboration, and innovation; and develop a publicly accessible central repository for autoimmune disease research. Currently, several ICOs support autoimmune research in alignment with their individual mission areas, leading to significant advances in autoimmune disease research across multiple disease areas. In developing an NIH-wide Strategic Plan for Autoimmune Disease Research, the OADR and ORWH will collaborate across ICOs to identify opportunities for synergistic innovation focused on areas of autoimmune disease research that will benefit from multi-ICO partnerships and opportunities to catalyze cross-cutting research.
- Objective 1: Research areas that would benefit from cross-cutting, collaborative research (these areas may include basic or translational research, clinical research, health services research, population science, data science, preventive research, biomedical engineering, and other areas of research).
- Objective 2: Opportunities to advance collaborative, innovative, or interdisciplinary areas of autoimmune disease research.
- Objective 3: Opportunities to improve outcomes for individuals living with autoimmune diseases including NIH-designated health disparity populations, populations and individuals with rare diseases, and specific populations that have been historically underrepresented in research and clinical trials.
- Objective 4: Cross-cutting areas that are integral to advancing autoimmune disease research at the NIH including development of a publicly accessible central repository for autoimmune disease research, sex- and gender-intentional research design across all stages of research, and engagement of all populations in research and clinical trials.
As directed by Congress, the OADR is also proceeding with portfolio analysis including all the autoimmune diseases listed in the NASEM report8 to better understand gaps and unmet needs in the current portfolio of autoimmune disease research across the NIH. This is a monumental effort given the inclusion of more than 140 distinct conditions. Analyzing and integrating data from portfolio analysis into the strategic planning process will facilitate the identification of gaps and needs within the field of autoimmune disease research, and these data will be used to inform the funding strategy for the OADR moving forward.
Of interest to the autoimmune community, the ORWH has been involved in two additional initiatives focused on advancing women's health research that include autoimmune diseases in their priorities. In November 2023, the White House established the Women's Health Research Initiative in the office of the First Lady.15 This initiative aims to “improve women's health in the United States by accelerating research on the unique health needs of women across their lifespans, and therefore fundamentally change how we approach and fund women's health research.” Additionally, the Gate's Foundation Women's Health Innovation Opportunity Map 2023 highlights the importance of evaluating sex- and gender- related differences in the evolution and presentation of autoimmune disorders and responses to available therapies to inform the development of prevention, screening, diagnosis, and treatment options for women, with a specific focus on systemic lupus erythematosus, rheumatoid arthritis, osteoporosis, and autoimmune thyroid diseases.16
Conclusions
This is undoubtedly an exciting time for research in autoimmune diseases. The OADR is looking forward to receiving community input on the strategic planning process as we seek to complement efforts of the NIH institutes and centers in advancing autoimmune disease research and accelerating understanding into fundamental mechanisms of immune dysfunction and autoimmunity across the lifespan. Our hope is to build on the significant progress already being made in the preclinical and clinical arena and provide focused, coordinated, and collaborative resources that allow the NIH to respond to the unmet needs of autoimmune disease research, translating these investments into improved outcomes for patients living with autoimmune disease.
AUTHOR CONTRIBUTIONS
Drs Shanmugam and Clayton drafted the article, revised it critically for important intellectual content, and approved the final version to be published.
Supporting Information
REFERENCES
中文翻译：
自身免疫性疾病研究办公室简介
介绍
尽管自身免疫性疾病的确切患病率尚不清楚，但估计表明它们影响着 7% 至 8% 的美国人口。1-3由于报告方面的挑战，自身免疫性疾病的整体死亡率数据不完整。然而，2000 年的一项研究评估了 24 种自身免疫性疾病的综合死亡率数据，结果表明，总的来说，这些疾病导致的死亡将使自身免疫性疾病成为女性死亡的主要原因之一。4报告还表明，随着时间的推移，自身免疫性疾病的发病率不断增加。5最近一项针对英国 2200 万人的人群队列研究发现，在近 20 年的时间里，有 4.45% 的人对最常见的 19 种自身免疫性疾病中的一种进行了新诊断。在这些人中，63.9% 是女性，6人，总共检查的 19 种自身免疫性疾病影响了 10.2% 的人口。在这项研究中，许多自身免疫性疾病的患病率随着时间的推移而增加。这项研究还概括了同时发生的自身免疫性疾病的存在，并且其他研究也证实了这一点，7为潜在的共同病因或发病机制提供了进一步的证据。
一段时间以来，大型流行病学研究引起了人们对如何评估自身免疫性疾病研究中的环境暴露的担忧。 2010 年召开的专家小组报告了与自身免疫性疾病相关的多种环境暴露，包括结晶二氧化硅、溶剂和其他化学品暴露、吸烟和辐射。1然而，由于了解暴露潜伏期、剂量以及整个生命周期中暴露的相互作用的复杂性，在自身免疫性疾病研究中研究环境暴露仍然具有挑战性。
2022 年，美国国家科学、工程和医学院 (NASEM) 对美国国立卫生研究院 (NIH) 与自身免疫性疾病相关的研究工作进行了分析，并在题为“加强 NIH 对自身免疫性疾病的研究”的报告中发表了他们的发现”。8部分基于本报告阐述的调查结果，国会通过《2023 财年综合拨款法》随附的联合解释声明，随后指示在妇女健康研究办公室内设立自身免疫性疾病研究办公室 (OADR) （ORWH）。据此，国会在 2023 年为新的 OADR 额外拨款 1000 万美元。自身免疫性疾病研究需要可靠的持续资金，以支持推进自身免疫性疾病研究所需的研究广度和深度。
众所周知，许多自身免疫性疾病的女性患病率较高9；尽管最近的研究表明 Xist 可能在自身免疫性疾病的性别差异中发挥一定作用，10 但自身免疫性疾病以女性为主的复杂性尚不清楚。了解生物系统中的性别差异，特别是在健康和疾病方面，是 ORWH 支持的工作重点。11, 12在自身免疫性疾病中，疾病活动在整个生命周期中的变化已得到广泛认可，并且历史上一直将其归因于荷尔蒙的变化。然而，人们越来越认识到，女性和男性的免疫反应在细胞水平上存在差异，与激素环境的变化无关，而这些差异的机制基础对于进一步了解女性患自身免疫性疾病的优势至关重要。13, 14将 OADR 置于 NIH 主任办公室的 ORWH 内，将独特地支持其在解决整个生命周期自身免疫性疾病及其对男性和女性影响方面的作用。
OADR 资金第一年的资助策略基于 NIH 研究所、中心和办公室 (ICO) 的建议，包括 NASEM 报告中列出的被认为属于自身免疫组合的疾病。8 2023 财年，OADR 为 12 个单独 ICO 总共提供了 41 个奖项。其中包括 15 个校外联合资助奖、3 个 R56 过桥资助奖、2 个加速药物合作伙伴自身免疫和免疫介导疾病奖、10 个校内联合资助奖、5 个校内科学奖学金和 6 个自身免疫性疾病合作团队规划 (EXACT-PLAN) 暴露体奖。 EXACT-PLAN 计划 (NOT-OD-23-112) 是与国家关节炎、肌肉骨骼和皮肤疾病研究所、国家环境健康科学研究所以及 ICO 合作者合作开发的，重点支持设计、开发、并实施未来的国家跨学科协作团队科学研究网络，该网络将推进自身免疫性疾病暴露组的研究。资助的奖项涵盖针对自身免疫性疾病的基础研究到转化科学、临床和公共卫生研究（图 1）。
在建立 OADR 时，国会进一步指示该办公室协调制定多机构和中心战略研究计划（以下称为 NIH 范围内的自身免疫性疾病研究战略计划）；确定新兴的创新领域和研究机会；协调和促进跨机构和中心的合作研究；每年评估 NIH 自身免疫性疾病研究组合；提供资源以支持规划、协作和创新；并开发一个可公开访问的自身免疫性疾病研究中央存储库。目前，多个 ICO 根据其各自的任务领域支持自身免疫研究，从而在多个疾病领域的自身免疫疾病研究方面取得了重大进展。在制定 NIH 范围内的自身免疫性疾病研究战略计划时，OADR 和 ORWH 将在 ICO 之间进行合作，以确定重点关注自身免疫性疾病研究领域的协同创新机会，这些领域将受益于多个 ICO 合作伙伴关系和促进跨领域研究的机会。
- 目标 1：将从交叉、协作研究中受益的研究领域（这些领域可能包括基础或转化研究、临床研究、卫生服务研究、人口科学、数据科学、预防性研究、生物医学工程和其他研究领域） 。
- 目标 2：推进自身免疫性疾病研究的协作、创新或跨学科领域的机会。
- 目标 3：有机会改善自身免疫性疾病患者的治疗结果，包括 NIH 指定的健康差异人群、患有罕见疾病的人群和个人，以及历史上在研究和临床试验中代表性不足的特定人群。
- 目标 4： NIH 推进自身免疫性疾病研究不可或缺的交叉领域，包括开发可公开访问的自身免疫性疾病研究中央存储库、跨所有研究阶段的性别意向研究设计以及所有人群的参与在研究和临床试验中。
根据国会的指示，OADR 还正在进行组合分析，包括 NASEM 报告8中列出的所有自身免疫性疾病，以更好地了解 NIH 当前自身免疫性疾病研究组合中的差距和未满足的需求。鉴于包含 140 多个不同的条件，这是一项巨大的努力。分析组合分析的数据并将其整合到战略规划过程中，将有助于识别自身免疫性疾病研究领域的差距和需求，这些数据将用于为 OADR 今后的资助策略提供信息。
引起自身免疫界关注的是，ORWH 还参与了另外两项举措，重点是推进妇女健康研究，其中将自身免疫性疾病列为优先事项。 2023年11月，白宫在第一夫人办公室设立了妇女健康研究计划。15该倡议旨在“通过加快对女性一生中独特健康需求的研究来改善美国女性的健康，从而从根本上改变我们处理和资助女性健康研究的方式。”此外，盖茨基金会 2023 年女性健康创新机会图强调了评估自身免疫性疾病的演变和表现中的性别和性别相关差异以及对现有疗法的反应的重要性，以便为预防、筛查、诊断和治疗方案的制定提供信息针对女性，特别关注系统性红斑狼疮、类风湿性关节炎、骨质疏松症和自身免疫性甲状腺疾病。16
结论
对于自身免疫性疾病的研究来说，这无疑是一个激动人心的时刻。 OADR 期待在战略规划过程中收到社区的意见，因为我们寻求补充 NIH 研究所和中心的努力，推进自身免疫性疾病研究并加速对整个生命周期免疫功能障碍和自身免疫的基本机制的理解。我们希望以临床前和临床领域已经取得的重大进展为基础，提供集中、协调和协作的资源，使 NIH 能够应对自身免疫性疾病研究未满足的需求，将这些投资转化为改善患者的治疗结果患有自身免疫性疾病。
作者贡献
尚穆根博士和克莱顿博士起草了这篇文章，对重要的知识内容进行了批判性修改，并批准了最终版本的出版。
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