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2 Background on Autoimmune Diseases
Pages 31-94

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From page 31...
... . In 1993, Rose and Bona reevaluated Witebsky's postulates2 defining autoimmune disease, and proposed three levels of evidence to establish that a human disease is autoimmune in origin, including direct evidence by transfer of disease with pathogenic autoantibody or autoreactive T cells, indirect evidence 1 In recent years, evidence of innate immune mechanisms that recognize and respond to damage to self-tissues has blurred self/non-self distinctions (Abbas et al., 2004; Rose and Mackay, 2014)
From page 32...
... . In fact, for most immune-mediated inflammatory diseases such as atherosclerosis, and prototypical autoimmune diseases such as multiple sclerosis, the innate and adaptive immune systems both play a role in promoting disease, leading to the notion of a spectrum or continuum of autoinflammatory-autoimmune diseases (Hedrich, 2016; McGonagle and McDermott, 2006)
From page 33...
... 2016–2018 triennial fiscal report to Congress discusses research applicable to autoimmune diseases in general as well as research on specific diseases, including SLE, multiple sclerosis, type 1 diabetes, myasthenia gravis, scleroderma, rheumatoid arthritis, myositis, juvenile idiopathic arthritis,5 alopecia areata, psoriasis, pemphigus vulgaris, BACH2-related immunodeficiency and autoimmunity (BRIDA) , and inflammatory bowel diseases (IBD)
From page 34...
... Use of Autoimmune Disease Definitions in Research Both the clinical criteria and biologic mechanism approaches to disease classification play a role in research efforts to better understand autoimmune disease. Sociological and clinical research studies, including those that NIH supports, define autoimmune diseases narrowly, requiring consensus diagnostic and classification criteria.
From page 35...
... Finding: Physicians and clinical researchers classify autoimmune diseases according to symptoms and laboratory abnormalities; basic science researchers classify autoimmune diseases according to more inclusive biological mechanisms. Lack of a consensus vocabulary impedes optimal research design and patient care.
From page 36...
... .There is great research interest in understanding how sex hormones regulate the immune response. Endocrine-disrupting chemicals such as phenols, parabens, and phthalates may influence sex differences in autoimmune diseases by altering sex hormone levels and/or ratios (Bruno et al., 2019; Castro-Correia et al., 2018; Edwards et al., 2018; Popescu et al., 2021)
From page 37...
... . Given the committee's focus on the effect of sex hormones and sex chromosomes on inflammation in relation to autoimmune disease pathogenesis, the committee chose to assume that most of the studies cited in this report involve biological sex differences.
From page 38...
... There is no mandatory reporting system or national registry for autoimmune diseases. Much of the available incidence and prevalence data come from countries other than the United States with health care systems covering the entire population (Eriksson et al., 2013; Munk Nielsen et al., 2019; Pasvol et al., 2020; Wei et al., 2018)
From page 39...
... . Based on the prevalence rates in Table 2-1, this suggests that Sjögren's disease may occur more than 20 times more fre quently when co-occurring with other autoimmune diseases than when diagnosed alone.
From page 40...
... • For multiple sclerosis, prevalence data from 2008 to 2010 are available from a study using three public (Veterans Administra tion, Medicare, and Medicaid) and three private administrative health claims databases collectively covering 125 million U.S.
From page 41...
... Death certificates can provide population-level data on mortality from autoimmune diseases, but they are not a good source of data pertaining to occurrence of chronic conditions that are not associated with acute mortality risks, such as most autoimmune diseases. Death certificates include information on immediate and underlying causes of death, with an additional field for 7 U.S.
From page 42...
... other significant conditions contributing to the death. However, the completeness and accuracy of this assessment, particularly for deaths relating to autoimmune diseases, is low: studies have demonstrated considerable under-reporting of autoimmune diseases as a cause of death, with no mention of an underlying condition in 40 to 80 percent of deaths of people enrolled in clinical cohort studies of SLE and rheumatoid arthritis (Calvo-Alén et al., 2005; Molina et al., 2015)
From page 43...
... As noted previously, the committee did not consider studies using self-reported data, without medical record review. that used death certificate data concluded that "Systemic autoimmune diseases constitute a rare group of causes of death, but contribute to mortality through multiple comorbidities.
From page 44...
... Estimates of Overall Prevalence of Autoimmune Diseases In 1997, a compilation and analysis of studies reporting incidence or prevalence data for diseases estimated that at least one autoimmune disease would occur in approximately 8.5 million U.S. residents, or 3.2 percent of the population (Jacobson et al., 1997)
From page 45...
... Epidemiology of Select Autoimmune Diseases Prevalence Rates Among the most common autoimmune diseases are celiac disease, rheumatoid arthritis, and psoriasis, with prevalence rates approximately 790 to 939 per 100,000 and approximately 2.3 to 2.5 million U.S. residents living with each of these diseases; IBD, with a prevalence rate of approximately 500 per 100,000; multiple sclerosis, with prevalence rates of approximately 300 per 100,000; and type 1 diabetes, with a prevalence rate of approximately 190 per 100,000 (Table 2-1)
From page 46...
... In children and adolescents, the incidence or prevalence of two of the most common autoimmune diseases, IBD and type 1 diabetes, appears to be increasing in the United States since 2000 (Table 2-2)
From page 47...
... Total Source Period in 2020a Sjögren's disease Population-based study Manhattan, NY, ≥ 18 13.1 21.1 3.5 35,370 (primary) b using Manhattan Lupus 2007 Surveillance Program Registry Systemic lupus Population-based study GA, MI: 2002– All ages 72.8 128.7 14.6 206,000 erythematosus using data from 4 CDC 2004 SLE registries and Indian CA, Manhattan, Health Service NY and Indian Health Service: 2007–2009 Antiphospho- Population-based study, MN 2001–2015 ≥ 18 50 51 48 123,000 lipid syndrome Rochester Epidemiology Project Rheumatoid Population-based, Kaiser Southern, CA ≥ 18 890.0 1326.0 387.0 2,403,000 arthritis Permanente, patient 2014 electronic records continued PREPUBLICATION COPY -- Uncorrected Proofs 47
From page 48...
... Total Source Period in 2020a Psoriasis Population-based study, Northern, CA, ≥ 18 939.0 No sex No sex 2,535,000 Kaiser Permanente, patient 2009 difference difference electronic, computerized reported reported records Population-based study, U.S. < 18 128.0 146.0 110.0 94,768 Truven Health, patient 2015 electronic, computerized records Inflammatory bowel diseasec Ulcerative colitis Retrospective cross- U.S.
From page 49...
... < 20 193.0 193.0 193.0 178,000 SEARCH data from five 2009 participating centers in CA, CO, OH, SC, WA and select American Indian reservations a U.S. total population estimates for Sjögren's disease, rheumatoid arthritis, psoriasis, primary biliary cholangitis were calculated by applying total prevalence rate to 2020 U.S.
From page 50...
... If these individuals are included, prevalence of all Sjögren's disease would be estimated to be on the order of 800,000 in the United States in 2020. However, this figure does not account for individuals with Sjögren's disease and other systemic autoimmune diseases (e.g., dermatomyositis, systemic sclerosis)
From page 51...
... study using Rochester MN rates, with higher values Epidemiology Project 1976–2015 around 1990, 2005, data and 2015, with overall increasing trend (p=0.005) Antiphospholipid Population-based Olmstead County, ≥ 18 No trends observed -- syndrome study using Rochester MN Epidemiology Project 2001–2015 data Rheumatoid Population-based Olmstead County, ≥ 18 Increased in women from -- arthritis study using Rochester MN 1995 to 2007 by about 2.5 Epidemiology Project 1995–2007 percent per year data Population-based Southern, CA ≥ 18 Average annual increase -- study using Kaiser 1995–2014 from 1995 to 2014 was PREPUBLICATION COPY -- Uncorrected Proofs Permanente, patient 3 percent (95 percent CI electronic records - 4 percent, 10 percent)
From page 52...
... ≥ 18 -- Increased from 214.9 sectional study using 2007–2016 to 478.4 per 100,000 two health claims databases Increased from 33.0 to 2–17 -- 77.0 per 100,000
From page 53...
... in women; from 7.2 to 15.4 per 100,000 in men; total rate change, from 21.7 to 39.2 per 100,000 Multiple sclerosis Population-based study Ontario, Canada ≥ 20 Generally stable except Increased from 157 to using Province of 1996–2013 for short-term increase 265 per 100,000 Ontario administrative 2010–2013 PREPUBLICATION COPY -- Uncorrected Proofs health data 53 continued
From page 54...
... (Medicaid < 18 -- Increased from 129 to PREPUBLICATION COPY -- Uncorrected Proofs using MarketScan population) 234 per 100,000 Multi-State Medicaid 2002–2016 Claims Database
From page 55...
... ; rheumatoid arthritis (1) (Myasoedova et al., 2010)
From page 56...
... . Demographic Patterns with Respect to Disease Risks Many, but not all, autoimmune diseases affect women predominantly (Figure 2-1)
From page 57...
... There was little difference in rates between males and females for Crohn's disease, but for ulcerative colitis, rates in males were somewhat higher than in females. Health Disparities in Autoimmune Diseases There are known disparities in the incidence, prevalence, severity, prognosis, outcomes and care related to autoimmune diseases.
From page 58...
... b) FIGURE 2-2  Incidence rates of four autoimmune diseases by age and sex in Olmsted County, Minnesota.
From page 60...
... . With respect to racial and ethnic disparities in incidence or prevalence of disease, it is important to note that no single pattern describes the patterns seen among the autoimmune diseases; for some diseases, the highest rates occur among Black individuals, while for other diseases, the highest rates occur in White individuals (Figure 2-3)
From page 61...
... A Prevalence of systemic lupus erythematosus (females)
From page 62...
... 62 ENHANCING NIH RESEARCH ON AUTOIMMUNE DISEASE FIGURE 2-3 Continued PREPUBLICATION COPY -- Uncorrected Proofs
From page 63...
... The committee believes that these striking variations in sex, race, and age patterns among autoimmune diseases are worthy of further research. Finding: There is a lack of population-based data from diverse popu lations to accurately assess the incidence, prevalence, lifetime risk, epidemiologic trends, and the extent of the impact of autoimmune diseases on the U.S.
From page 64...
... . Investigators have not studied all combinations of autoimmune diseases at the population level, and key studies on autoimmune coexistence within individuals have focused largely on multiple sclerosis, rheumatoid arthritis, autoimmune PREPUBLICATION COPY -- Uncorrected Proofs
From page 65...
... A notable exception to the premise of clustering was between multiple sclerosis and rheumatoid arthritis, where findings suggested an inverse association. Importantly, this study predated the availability in the United Kingdom of tumor necrosis factor inhibitors, used today to treat some autoimmune diseases, which otherwise could have confounded results given reports of multiple sclerosis in association PREPUBLICATION COPY -- Uncorrected Proofs
From page 66...
... Systemic Lupus Erythematosus Rheumatoid Arthritis FIGURE 2-4  Sex-specific standardized incidence ratios and 95% confidence intervals for the existence of coexisting autoimmune diseases within each index disease category (a standardized incidence ratio of 100 indicates unity)
From page 67...
... Systemic Sclerosis FIGURE 2-4  Continued PREPUBLICATION COPY -- Uncorrected Proofs 67
From page 68...
... Aside from the combinations of autoimmune diseases detected within individuals described above, additional disease associations reported in family studies include: polyarteritis nodosa, Addison's disease, Crohn's disease, and "autoimmune diseases in general" in relatives of individuals with multiple sclerosis; autoimmune thyroid diseases and "autoimmune diseases in general" for SLE; "autoimmune diseases in general" for Sjögren's disease; and autoimmune thyroid diseases and "autoimmune diseases in general" for idiopathic inflammatory myopathy (Cooper et al., 2009)
From page 69...
... . In other autoimmune diseases, absolute and relative mortality risks are lower.
From page 70...
... . Flare-ups of symptoms or disease activity, often requiring hospitalization, are common in many autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, SLE, and IBD (Morales-Tisnes et al., 2021; Panopalis et al., 2012)
From page 71...
... Multiple physiological processes may contribute to fatigue in autoimmune diseases including inflammatory activation of the immune system that affects the peripheral and central nervous systems (Lee and Giuliani, 2019b; Morris et al., 2015)
From page 72...
... Another effect of autoimmune diseases, particularly during the young and middle-aged adult years, is employment-related disability. Studies of people with IBD, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic sclerosis, and SLE report partial or full work disability, with one cohort study of persons with early rheumatoid arthritis observing a work disability rate of 28 percent at study start and 44 percent 15 years later (Eberhardt et al., 2007; Orbai et al., 2021; Raggi et al., 2016; Scofield et al., 2008; Sharif et al., 2011; van der Valk et al., 2014b)
From page 73...
... . Finding: Autoimmune diseases are associated with an increased risk of cancer.
From page 74...
... . Finding: There is little data on the direct and indirect costs in the United States of specific autoimmune diseases and of autoimmune diseases overall.
From page 75...
... . The epidemiologic study of autoimmune diseases using a life-course framework emphasizes a longitudinal approach inclusive of all life stages, linking a multiplicity of exposures across the life course to later health outcomes.
From page 76...
... Both the innate and adaptive immune systems are involved in promoting autoimmune disease, and genetics, social and environmental exposures, and sex differences may contribute to the development or exacerbation of autoimmune diseases. There is no consensus definition of autoimmune disease.
From page 77...
... . Among the most common autoimmune diseases are celiac disease, rheumatoid arthritis, psoriasis, IBD, and type 1 diabetes.
From page 78...
... . The study of co-occurring autoimmune diseases in individuals has focused largely on multiple sclerosis, rheumatoid arthritis, autoimmune thyroiditis, type 1 diabetes, and IBD, with several combinations occurring at greater than expected rates.
From page 79...
... 2012. Common mechanisms of autoimmune diseases (the autoimmune tautolo gy)
From page 80...
... 2011. Racial and ethnic disparities in disease ac tivity and function among persons with rheumatoid arthritis from university-affiliated clinics.
From page 81...
... 2008. Autoimmune disease concomitance among inflammatory bowel disease patients in the United States, 2001-2002.
From page 82...
... 2015. The increased cardiovascular risk in patients affected by autoimmune diseases: Review of the various manifestations.
From page 83...
... 2021. Unrav elling the shared genetic mechanisms underlying 18 autoimmune diseases using a systems approach.
From page 84...
... 2018. Final adult height of patients with childhood-onset systemic lupus erythematosus: A cross sectional analysis.
From page 85...
... 1997. Epidemiology and estimated population burden of selected autoimmune diseases in the United States.
From page 86...
... 2022. Definition of autoimmunity & autoimmune disease.
From page 87...
... 2015. Patients with overlap autoimmune disease differ from those with ‘pure' disease.
From page 88...
... 2020. Systemic autoimmune disease among adults exposed to the September 11, 2001 terrorist attack.
From page 89...
... 2008. Autoimmune diseases in patients with multiple scle rosis and their first-degree relatives: A nationwide cohort study in Denmark.
From page 90...
... 2020. Sex differences in systemic lupus erythematosus: Epidemiology, clinical considerations, and disease pathogenesis.
From page 91...
... 1993. Defining criteria for autoimmune diseases (Witeb sky's postulates revisited)
From page 92...
... 2006. Autoimmune diseases co occurring within individuals and within families: A systematic review.
From page 93...
... 2018. Depression as a risk factor for the development of rheumatoid arthritis: A population-based cohort study.
From page 94...
... Inflammatory Bowel Diseases 26(4)


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