3

Overview of Select Autoimmune Diseases

As noted in Chapter 1, the committee focused a literature review on a select number of autoimmune conditions. These autoimmune diseases—Sjögren’s disease, systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD), celiac disease, primary biliary cholangitis (PBC), multiple sclerosis, type 1 diabetes, and autoimmune thyroid disease—serve as representatives of this heterogeneous class of disorders. As explained at greater length in Chapter 1, the committee included diseases that are overrepresented in women, affect multiple systems, and are associated with coexisting morbidity. The committee selected diseases that collectively can represent the spectrum of autoimmune diseases. The committee also took into account the congressional language requesting the study and the availability of data to assess the National Institutes of Health (NIH) research portfolio.

There are no known cures for autoimmune diseases. Autoimmune diseases may affect any part of the body and sometimes affect many parts or result in systemic features. Classically, autoimmune diseases have been organized or named based on the organ system or tissue affected, and health care providers specializing in areas of medicine that focus on those organ systems are typically the ones who diagnose and manage these diseases. However, the specific mechanisms that dictate which organ an autoimmune disease affects when it develops are not fully understood, and many similarities, including genetic susceptibility and disease mechanisms, exist among autoimmune diseases that affect different organ systems.

While an immune response that targets different organ systems or self-antigens characterizes each disease, classifying diseases by clinical manifestations and laboratory tests that detect autoantibodies, for example, may not be the most accurate way to guide therapeutic decision making, given that the presence of similar clinical manifestations or autoantibodies can result from different immunological mechanisms. For example, a recent study of seven systemic autoimmune diseases—Sjögren’s disease, SLE, APS, rheumatoid arthritis, systemic sclerosis, mixed connective tissue disease, and undifferentiated connective tissue disease—reported complex gene expression and epigenetic analyses that enabled the investigators to arrange these seven diseases into four different molecular clusters, with each disease represented across all four clusters (Barturen et al., 2021). Three clusters represented three different pathologic immunological pathways and mechanisms associated with disease activity, while the fourth “undefined” cluster was more similar to that of healthy controls. Over time, most individuals remained within their original cluster or alternated between their original pathologic cluster and the undefined/healthy-control-like cluster. The authors suggest that defining such clusters may help to guide therapies that are more likely to effectively modulate the immune pathways most relevant for a given individual’s autoimmune disease manifestations. Similarly, cluster analysis may predict the trajectory of rheumatoid arthritis (RA-MAP Consortium, 2021).

In this chapter, the committee provides an overview of select autoimmune diseases to highlight the complexities of autoimmune diseases, and it has structured the review of each disease to reflect the committee’s charge as directed in the statement of task for this study. To illustrate some common complexities—including heterogeneity, targeting of ubiquitous self-antigens, and an absence of adequate diagnostic biomarkers or effective therapies—the chapter begins with Sjögren’s disease, a systemic autoimmune disease that has some organ-specific features, is most commonly diagnosed in women, and often co-occurs with other autoimmune diseases. After Sjögren’s disease, the chapter will provide information on three systemic autoimmune diseases—SLE, APS, and rheumatoid arthritis—followed by discussions on autoimmune diseases that affect a specific tissue or organ system, including the skin (psoriasis), the gastrointestinal system (IBD, celiac disease, and PBC), the central nervous system (CNS) (multiple sclerosis), and the endocrine system (type 1 diabetes and autoimmune thyroid disease).

Chapter 2 provides data on the incidence and prevalence of these diseases, and this chapter provides information on sex, age, racial, and ethnic disparities. In addition, Appendix D provides more detailed epidemiologic information for each disease.

SJÖGREN’S DISEASE

Sjögren’s disease (often referred to as Sjögren’s syndrome, though the term syndrome is less accurate) is a chronic autoimmune disease with organ-specific and systemic features (Baer and Hammitt, 2021). Sjögren’s disease has no well-defined treatments to slow the autoimmune process (Vivino et al., 2019), which can negatively affect an individual’s quality of life (Cornec et al., 2017; McCoy et al., 2021; Saldanha et al., 2020; Sivakumar et al., 2021). The classic features of Sjögren’s disease include dryness of the mouth and eyes that results from a progressive autoimmune attack directed toward the saliva-producing (salivary) and tear-producing (lacrimal) glands. The consequences of this attack range from discomfort to vision-threatening ocular damage, loss of teeth resulting from extensive dental caries, and difficulty carrying out common activities such as chewing, swallowing, and talking. Sjögren’s disease often causes dryness of other parts of the body in addition to the mouth and eyes, including nasal mucosa (causing irritation and frequent nosebleeds), lower airways (causing chronic dry cough), skin (causing itchiness), and vaginal mucosa (causing general discomfort as well as pain during sexual intercourse and decreased sexual satisfaction) (Vivino et al., 2019). Besides providing moisture and lubrication, secretions from glands in these tissues help prevent infections, so gland dysfunction increases risk of infection.

Beyond dryness, many individuals with Sjögren’s disease develop severe pain and fatigue. The pain may result from autoimmune inflammation of the joints (arthritis) or muscles (myositis), but more commonly it occurs without inflammation of the affected areas, making it more difficult to formally assess or treat. The fatigue that accompanies Sjögren’s disease is also poorly understood and is difficult to treat. Together, dryness, pain, and fatigue contribute to functional disability, decreased work productivity, and overall decreased quality of life (Cornec et al., 2017; McCoy et al., 2021; Saldanha et al., 2020; Sivakumar et al., 2021; Vivino et al., 2019). In addition, Sjögren’s disease may affect any organ either by direct autoimmune attack or as a result of circulating immune complexes depositing in an organ (Vivino et al., 2019). These extra-glandular manifestations may affect joints, muscles, blood cells, kidneys, lungs, skin, the nervous system, and the gastrointestinal system.

The slowly progressive dryness features may not lead an individual to seek medical care, though hormone changes associated with menopause greatly exacerbate the already developing dryness, prompting evaluation for Sjögren’s disease. Earlier diagnosis may occur when other organs are affected, leading an individual to seek medical care for the extra-glandular manifestations. However, health care providers may fail to consider Sjögren’s disease as a diagnosis when there is a lack of profound dryness

at presentation or when the main symptoms are musculoskeletal pain and fatigue.

Epidemiology and Impact

Information on disparities in the epidemiology of Sjögren’s disease can be found in Box 3-1.

Complications, Other Morbidity, and Long-Term Consequences

Sjögren’s disease commonly co-occurs with other autoimmune diseases. Among the autoimmune diseases that most often co-occur with Sjögren’s disease are autoimmune thyroid disease, rheumatoid arthritis, SLE, systemic sclerosis, and autoimmune liver disease, including primary biliary cholangitis (Anaya et al., 2016). Beyond co-occurring autoimmune diseases, complications associated with Sjögren’s disease include cardiovascular disease, lymphoma, and depression (Beltai et al., 2020; Ekström Smedby et al., 2008; Westhoff et al., 2012). Sjögren’s disease autoimmunity confers a 4- to 10-fold increased risk of lymphoma (Ekström Smedby et al., 2008).

Together with the profound dryness, pain, fatigue, and other disease-specific effects described above, these complications and coexisting conditions contribute to the overall decrease in quality of life and work productivity and increase in health care cost in individuals with Sjögren’s disease (Miyamoto et al., 2019). However, there are no reports in the literature of detailed studies on the life course of individuals with Sjögren’s disease to more specifically define the contributions of each possible manifestation on life course.

In pregnant women with Sjögren’s disease, anti-Sjögren’s syndrome–related antigen A autoantibodies (SSA/Ro) autoantibodies associated with Sjögren’s disease can cross the placenta and cause neonatal lupus in the developing fetus. While most neonatal lupus manifestations resolve without long-term consequences once the mother’s antibodies have been cleared from the infant’s circulation, the autoantibodies may damage the conduction system of the fetal heart, resulting in congenital heart block that causes severe reduction in fetal heart rate and may lead to fetal death or the need for pacemaker placement soon after birth (Brucato et al., 2011). Complete heart block occurs in only 1–2 percent of neonatal lupus cases, but the risk increases to 15 percent for subsequent pregnancies. The diagnosis of neonatal lupus in the baby often prompts initiating tests of the mother for Sjögren’s disease-associated antibodies, and the formal diagnosis of Sjögren’s disease, based on clinical findings rather than autoantibodies alone, may not occur for months to years later.

Economic Impact

Disability, decreased work productivity, decreased quality of life, and direct health care costs contribute to the overall economic impact of Sjögren’s disease (Uchino and Schaumberg, 2013). In the United States, a retrospective observational study using claims databases reported a 40 percent increase in all-cause health care costs in the year after diagnosis compared with the year prior to diagnosis (Birt et al., 2017). The average

cost during the first year following diagnosis of Sjögren’s disease was $20,416 per person. One study found similar economic impact in other countries (Miyamoto et al., 2019).

Risk Factors and Etiology

The X chromosome plays a significant role in the risk of developing Sjögren’s disease. Females with the standard chromosomal count have a greater risk than males with the standard chromosomal count. However, the prevalence of Sjögren’s disease was approximately three times higher than in the general population among females with an extra X chromosome (Liu et al., 2016) and 15 times higher in males with an extra X chromosome (Harris et al., 2016). As in other systemic rheumatic diseases, genetic variants associated with Sjögren’s disease are complex and include genes in the region of chromosome 6 that codes for human leukocyte antigens (HLA), as well as other genes associated with immune function (Imgenberg-Kreuz et al., 2021; Thorlacius et al., 2020).

Epigenetic modifications may also predispose an individual to develop Sjögren’s disease (Imgenberg-Kreuz et al., 2019). Among environmental risk factors, studies have focused on microbial infections, such as Epstein-Barr virus (EBV), cytomegalovirus, and hepatitis C (Björk et al., 2020). Despite associations with different viral or bacterial infections, research has not established a causative role for infections in the development of Sjögren’s disease. Studies have also implicated stress, low levels of vitamin D, and various organic chemical factors in the development of Sjögren’s disease, but the data do not suggest clear associations with the disease (Björk et al., 2020).

As with other autoimmune diseases, the immune response targeting self-antigens in Sjögren’s disease is complex. While the specific autoimmune mechanisms in Sjögren’s disease are not fully understood, research has identified several antigens as targets of autoantibodies (Fayyaz et al., 2016; Martín-Nares and Hernández-Molina, 2019). For diagnostic purposes, the autoantibodies most commonly assayed include those often found in other autoimmune diseases, such as antinuclear antibodies and rheumatoid factor. Autoantibodies have been detected in blood samples up to 20 years prior to diagnosing Sjögren’s disease (Theander et al., 2015).

The autoantibodies most specific for Sjögren’s disease target the Ro52, Ro60, and La48¹ antigens, though the antigens are ubiquitously expressed and autoantibodies specific for these proteins have been detected in other autoimmune diseases (Zampeli et al., 2020). All three of these proteins

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¹ These are also called Sjögren’s-syndrome-related antigen A/Ro (SSA/Ro) and Sjögren’ssyndrome-related antigen B/La (SSB/La).

reside inside cells, making it unclear how autoantibodies access them. The association of anti-Ro52, anti-Ro60, and anti-La48 antibodies in Sjögren’s disease and other autoimmune diseases, as well as in driving neonatal lupus manifestations, is still incompletely understood. Given their ubiquitous expression and association with so many different autoimmune manifestations and diseases, it is worth considering further studies to identify the factors contributing to the immune system targeting these antigens and the subsequent effects of the autoantibodies on immune regulation or dysregulation as a potential pathogenic component of the autoimmune disease process.

Diagnostic Tools

Diagnosing Sjögren’s disease is not straightforward given the lack of a single diagnostic test or biomarker and that no well-accepted diagnostic criteria exist. Classification criteria developed for use in identifying people with Sjögren’s disease for clinical trials often guide diagnosis, but these criteria were not intended to accurately diagnose all individuals with Sjögren’s disease (Vivino et al., 2019).

Diagnostic testing includes measuring the cardinal features of Sjögren’s disease: autoantibodies as biomarkers, inflammation of the affected glands on biopsy, salivary gland biopsy, salivary gland function, and lacrimal gland function. Imaging the glands with magnetic resonance imaging (MRI) or ultrasound may also provide supportive information. Ultimately, diagnosis depends on the opinion and experience of the physician, but generally requires a combination of abnormal test results, with either autoantibodies specific for Sjögren’s disease or positive lip biopsy required to support a Sjögren’s disease diagnosis.

The most reliable biomarker currently available is the anti-SSA/Ro antibody, which comprises two different antibodies targeting Ro52 and Ro60, but anti-SSA/Ro antibodies may be absent in up to 25 to 30 percent of individuals with Sjögren’s disease. Some studies have suggested that antinuclear antibodies and rheumatoid factor might also serve as biomarkers, though the utility of each in diagnosing Sjögren’s disease is a matter of debate. When these antibodies are absent, the diagnosis becomes more difficult, especially early in disease, such as in childhood, when features of dryness may be absent. The lack of more reliable biomarkers for early diagnosis represents a barrier to diagnosis, as well as a key gap in understanding the disease process.

Treatments and Prospects for Cures

Current treatments for the glandular manifestations of Sjögren’s disease aim to replace tears and saliva or to stimulate increased production

from the individual’s own glands, but these approaches do not alter the inflammatory response and are only moderately helpful in relieving dryness. Anti-inflammatory eye drops may help control the damage to the ocular surface, but again, they do not alter the ongoing systemic autoimmune response. No medications have been identified to adequately modulate the autoimmune response or to prevent progression from early stages of disease, such as in children or young adults, to the more profound dryness and associated complications that occur later in disease. Similarly, treatments for the progressive fatigue and musculoskeletal pain are lacking.

When extra-glandular manifestations develop, clinicians may consider immunomodulatory therapies commonly used to treat other autoimmune diseases. There are published consensus guidelines that aim to help direct therapeutic decisions based on manifestations (Lee et al., 2021; Ramos-Casals et al., 2020; Vivino et al., 2016). However, the U.S. Food and Drug Administration (FDA) has not approved any systemic immunomodulatory medications for treating Sjögren’s disease, and large clinical trials of potential therapies have generally failed to reach primary endpoints despite promising preliminary data from earlier trials (Fox and Fox, 2016). It is not clear whether these failures are a result of suboptimal selection of individuals with Sjögren’s disease or endpoint measures, varied disease mechanisms, or lack of well-established disease activity biomarkers. Given the lack of adequate treatments and incomplete understanding of the pathogenesis of Sjögren’s disease, no realistic prospects for cures exist at this time.

Heterogeneity in Disease

The committee determined that Sjögren’s disease is an example of the types of heterogeneity that occur in autoimmune disease. The degree of heterogeneity in many aspects of Sjögren’s disease is a barrier to more reliable diagnosis and effective treatments. Studies have found variations in clinical features associated with geolocation, ethnicity, and ancestry (Brito-Zerón et al., 2017; Taylor et al., 2017). One recent study used hierarchical cluster analysis to stratify people with Sjögren’s disease into four clusters based on the severity of common symptoms of the condition (pain, fatigue, dryness, anxiety, and depression) and found significant differences among clusters in immunological measures, including autoantibodies, blood lymphocyte counts, and measures of B cell activity (Tarn et al., 2019). Applying this clustering technique to participants of prior clinical trials that failed to demonstrate efficacy did identify treatment effects within specific clusters. This retrospective analysis suggests that

the heterogeneity of features contributed to the lack of efficacy in these failed clinical trials, which considered only the total study population.

From a pathophysiologic perspective, investigators demonstrated the heterogeneity of the interferon signature in the labial minor salivary gland biopsy specimens of individuals with Sjögren’s disease (Hall et al., 2015). Specifically, they found a high interferon signature in 58 percent of the individuals, and further analyses demonstrated that among these individuals the interferon signature was dominated by type I interferon in 29.0 percent of the biopsy samples, type II interferon in 35.5 percent of the samples, or a combination of type I and type II interferon in 35.5 percent of the samples. Moreover, several immunological measures, including white blood cell counts, immunoglobulin levels, autoantibodies, degree of salivary gland inflammation, and measures of gland dysfunction, varied between individuals with high or low interferon pathways, and some features also varied based on the type of interferon dominating the interferon signature pattern. These findings suggest that different immunological pathways may drive different clinical and laboratory parameters, contributing to disease heterogeneity.

Along these lines, a recent study of multi-omic profiling of whole blood samples from individuals with Sjögren’s disease defined a molecular classification strategy that led to clustering of individuals in four cohorts based on gene expression, genetic risk loci, epigenetics, immunologic analyses—cytokine profiles and flow cytometric-based characterization of immune cells—and clinical data (Soret et al., 2021). This study also found interferon signatures within three of the four clusters that included differing contributions from type I or type II interferons, depending on the cluster. Differences in cytokine and immune cell profiles suggested a greater contribution of acute inflammation in one cluster, which may have therapeutic implications.

Together these studies identify disease heterogeneity in immunological mechanisms, laboratory measures of disease, and clinical features. Better understanding and definition of disease heterogeneity may provide key insight to better direct specific immunomodulatory therapies for different clusters of individuals with Sjögren’s disease, a key step toward a personalized medicine approach for this disease.

Animal Models

Investigators have described and used a variety of animal models to study various aspects of the autoimmune process that occurs in Sjögren’s disease (Abughanam et al., 2021). While no one animal model perfectly recapitulates the human disease, several models develop spontaneous autoimmunity with features similar to Sjögren’s disease in humans,

including the characteristic lymphocyte-dominant inflammation of lacrimal or salivary glands, autoantibodies, and decreased production of tears and saliva. Several inbred mouse strains or genetically modified mouse strains spontaneously develop Sjögren’s disease-like disease, providing a model to study the early immunopathogenic mechanisms that cannot currently be studied in humans because of the lack of predictive biomarkers. Investigators have also used immunization of purified antigenic proteins or viral infection to induce Sjögren’s disease-like autoimmunity in other animal models.

Research Progress and Gaps

Despite the many gaps in understanding Sjögren’s disease, investigators have made considerable progress in defining genetic associations (Harris et al., 2016; Imgenberg-Kreuz et al., 2019; Liu et al., 2016), pathologic roles of innate and adaptive immunity (Chivasso et al., 2021), and mechanisms involved in the development of lymphomas in Sjögren’s disease (Stergiou et al., 2020). This progress has contributed to an increased awareness of Sjögren’s disease and an increase in clinical trials. However, key gaps remain as obstacles to early diagnosis and effective treatments.

One such barrier is the prolonged time between autoimmunity onset and diagnosis, resulting from the lack of highly sensitive diagnostic biomarkers and the lack of awareness of the early manifestations of disease among clinicians. Identifying early diagnostic biomarkers would aid in developing diagnostic criteria aimed specifically at diagnosis in the early stages of disease, or if possible, prior to the development of clinical features. Such predictive biomarkers would promote interventional studies to alter the disease course before the development of end-organ damage that may be difficult to reverse. The molecular characterization of Sjögren’s disease has contributed to defining key aspects of disease heterogeneity, but at present the different subtypes and specific mechanisms of Sjögren’s disease are not well defined. The prolonged course of autoimmunity leading to diagnosis and the lack of adequate surrogate endpoints make clinical trials less practical, and may be contributing significantly to the failure of clinical trials to meet study endpoints. However, identifying clinical features that would enable better classification of patients with different disease subtypes may enhance the feasibility and effectiveness of clinical trials. As noted above, a better characterization of the life course of individuals with Sjögren’s disease is needed.

Sjögren’s disease occurs at least as commonly (or more commonly) in individuals with other autoimmune diseases, including rheumatoid arthritis, SLE, and scleroderma, as it does in individuals without other autoimmune diseases, but specific studies aimed at identifying similarities

and differences in clinical features, genetics, immunological features, and disease course are lacking. Epidemiologic studies to define the incidence and prevalence of Sjögren’s disease regardless of the presence of co-occurring autoimmune diseases are greatly needed. In some individuals later diagnosed with Sjögren’s disease, the initial presentation occurs early, during or after pregnancy in the form of neonatal lupus, which can lead to a range of features in the infant resulting from the passage of autoantibodies characteristic of Sjögren’s disease to the fetus during development, as described above. Factors that contribute to the severity of features manifested in the infant are not well-defined, and factors that promote development of neonatal lupus, especially in previously asymptomatic mothers, as an initial manifestation of the presence of Sjögren’s disease-associated autoantibodies are poorly understood. Similarly, the specific mechanisms by which these antibodies cause neonatal lupus manifestations, which themselves are heterogeneous among affected individuals, may provide insight into potential pathologic contributions of these autoantibodies to individuals with Sjögren’s disease.

SYSTEMIC LUPUS ERYTHEMATOSUS

SLE, a systemic inflammatory illness, is the prototype systemic autoimmune disease, characterized by multi-organ inflammation (Vaillant et al., 2021). The disease is chronic, extremely heterogeneous in manifestation, and it affects mostly young women and disproportionately those of color. SLE can occur in children, most often during the teen years, and symptoms may be similar to those of adults but more severe (Cleveland Clinic, 2021). A distinctive sign of SLE, a facial rash in the shape of a butterfly that spreads across both cheeks, occurs in many but not all cases (Mayo Clinic, 2021b). Arthritis, rash, cytopenias, lupus nephritis, and neurologic abnormalities are the most common abnormalities signaling the presence of SLE. The disease may be lethal, but most people with SLE suffer unpredictable flares and spontaneous or treatment-induced remissions (Thanou et al., 2021) and suffer damage resulting from active disease and/or its treatment. Most flares, however, have no obvious inciting event.

Epidemiology and Impact

Information on disparities in the epidemiology of SLE can be found in Box 3-2.

Complications, Other Morbidity, and Long-Term Consequences

SLE affects every organ system; damage accrues through active inflammation, thrombosis, and repair and scarring processes. Individuals with SLE are subject to inflammatory disease such as pericarditis, valvulitis, and myocarditis (Fava and Petri, 2019; Wallace and Gladman, 2019); atherosclerotic disease including micro- or macrovascular myocardial infarction (Roman et al., 2003); stroke caused by vasculitis, thrombosis,

and atherosclerosis (Wallace and Gladman, 2019); and peripheral neuropathy (Fava and Petri, 2019). In addition, persons with the disease may experience renal failure resulting from glomerulonephritis, tubulointerstitial disease, hypertension, and/or vasculitis (Fava and Petri, 2019) as well as a modestly increased risk of lymphoma (Bernatsky et al., 2014). Side effects of treatment include coronary artery disease; retinopathy, including cataracts; osteoporosis; and osteonecrosis, bone death caused by poor blood supply, which can lead to fractures (Fava and Petri, 2019; Gladman et al., 2018; Kamphuis and Silverman, 2010; Wallace and Gladman, 2019). Premature atherosclerosis and bone-related complications, including osteoporosis and osteonecrosis, are important SLE-related complications. Prior to 1955, less than 50 percent of patients survived 5 years after diagnosis; now, 10-year survival exceeds 90 percent. This has resulted in an increased rate of reported musculoskeletal conditions (Kennedy and Khan, 2015).

Some patients may report that osteonecrosis causes a greater reduction in their quality of life than SLE as the underlying systemic disease. Treatment with high dose steroids can led to osteonecrosis and pain and reduced function can be severe, warranting surgical intervention such as joint replacements. After such surgery, such individuals can be at higher risk for implant infection, discharge to an inpatient facility, more expensive hospital bills, and increased blood transfusions than people without SLE (Singh and Cleveland, 2019).

People with SLE are also highly susceptible to bacterial, fungal, viral, and mycobacterial infections, primarily in the setting of aggressive therapy with corticosteroids and/or small molecule and biologic immunosuppressant agents, but occasionally in association with disease-induced severe leukopenia or lymphopenia (Fava and Petri, 2019). Patients suffer depression, anxiety, and psychosis caused by central nervous system disease, the effects of medications such as corticosteroids, and personal adaptation to living with an unpredictable, disabling, and painful disease (Roberts et al., 2018; Siegel et al., 2021; Zhang et al., 2017).

About 40 percent of people with SLE test positive for antiphospholipid antibodies (aPL) (Garcia and Erkan, 2018; Meroni and Tsokos, 2019). Between 20 and 40 percent of people with SLE have other autoimmune illnesses, such as autoimmune thyroid diseases (Klionsky and Antonelli, 2020) or Sjögren’s disease (Wallace and Gladman, 2019), or have features of other autoimmune illnesses such as overlapping thrombocytopenia, Raynaud’s syndrome, or rheumatoid arthritis, also known as “rhupus” (Antonini et al., 2020; Jia et al., 2017; Lockshin et al., 2015).

Pregnancies are high risk for some women with SLE, with most complications related to hypertension, renal disease, or antiphospholipid syndrome rather than to active SLE (Sammaritano et al., 2020). Preeclampsia

and premature birth are common complications as well. If the pregnancy is not complicated, children of mothers with SLE who do not have certain autoantibodies are born healthy. However, antiphospholipid antibodies predict preeclampsia and placental dysfunction that leads to fetal growth restriction and/or death. Anti-SSA/Ro and anti-SSB/La occur in all children with neonatal lupus syndrome, which occurs in a minority of children born to women who carry these antibodies (Yoshimi et al., 2012). Neonatal lupus is characterized by hepatitis, cytopenias, and rash, which are transient and common, and congenital heart block, which is permanent but rare (Diaz et al., 2021). Maternal autoantibodies persist in the mothers but not typically in babies beyond the first year of life (Zuppa et al., 2017). Except when the mother is taking contraindicated medications, breastfeeding is safe for both mother and child (Sammaritano et al., 2020).

Phenotypic heterogeneity—the differing presentations of SLE—precludes the ability to confidently predict disease progression. SLE is a lifelong illness, with 10-year survival rates of greater than 90 percent and continuing inflammation and illness- and treatment-related damage driving patient-specific outcomes (Reppe Moe et al., 2021; Singh and Yen, 2018). The illness is more episodic than progressive, with flares and remissions. Damage accrues in different organs at different rates and may vary based on severity of inflammation, differences in healing mechanisms and scarring, and differing effects of medication.

SLE severely affects quality of life in many ways. Most patients suffer fatigue and neurocognitive and musculoskeletal symptoms including pain and weakness (Natalucci et al., 2021; Olesinska and Saletra, 2018; Takase et al., 2021). SLE causes changes in body image as a result of SLE-related effects such as skin rashes and hair loss, and changes in mental status as a result of both the disease and its treatment (Olesinska and Saletra, 2018; Yoon et al., 2019). The disease adversely affects the individual’s family relations, personal relationships, physical fitness, and sexual activity (Olesinska and Saletra, 2018). Invisible symptoms may prompt disbelief in family, acquaintances, and even physicians. Coexisting diseases complicate evaluation and treatment of SLE. Recent studies of SLE indicate patients’ and physicians’ desire to see improved quality of life as a target of treatment (Kernder et al., 2020; Pereira et al., 2020; Shi et al., 2021) by non-pharmacological (Chang et al., 2021) and pharmacological interventions (Jolly et al., 2021).

Economic Impact

The economic costs of SLE are high, comprising both direct costs for delivery of medical care and indirect costs for lost employment productivity (Abu Bakar et al., 2020; Agarwal and Kumar, 2016), as well as

intangible costs resulting from pain and suffering. Studies of direct costs have shown that patients with SLE incur health care costs that are twice as high as a control population. Acute hospitalization accounts for up to 50 percent of these increased costs, followed by medications and physician visits (Panopalis et al., 2012). Higher costs are associated with SLE renal disease, higher disease activity, and impaired physical and mental function. In a large U.S. study of adults with SLE, total unadjusted costs were significantly higher among Medicaid-insured than commercially insured patients (Clarke et al., 2020; Panopalis et al., 2012).

As a significant cause of work disability in the United States, the indirect costs of SLE also convey a high individual and societal cost resulting from unemployment and decreased productivity. A longitudinal study found that 49 percent of adults with SLE in the southeastern United States experienced work loss over an average disease duration of 13 years. Those most affected had severe disease activity and organ damage, and Black residents were more likely than White residents to experience unemployment as a result of having SLE (Drenkard et al., 2014). In addition, for those individuals remaining employed, impaired work productivity was associated with severe fatigue, and neurocognitive and musculoskeletal symptoms.

Risk Factors and Etiology

The cause of SLE is unknown, though there appears to be a genetic contribution. Family histories of SLE and related autoimmune diseases are common in close relatives of individuals with SLE (Kuo et al., 2015). Twin studies show much higher concordance in identical than in fraternal twins (Block et al., 1975, 1976; Deapen et al., 1992; Reichlin et al., 1992). Many people with SLE have been found to have susceptibility genes that are thought to be contributory but not directly causal in the development of SLE. These include genetic variants in HLA and non-HLA coding regions, some of which have been found to play a role in immune regulation (Ghodke-Puranik and Niewold, 2015). In addition, many people once thought to have early-onset SLE are now known to have specific single-gene (monogenic) mutations, often in interferon pathways. Interferon pathway abnormalities are common. Examples are VEXAS syndrome and Aicardi-Goutière syndrome (Beck et al., 2020; Demirkaya et al., 2020). No consensus exists on whether monogenic SLE-like illnesses should be classified as a subset of SLE or as separate genetic disorders.

Other than family history, there is limited information on risk factors or etiologies for initiation of SLE, though exogenous events such as infection or extensive ultra-violet light exposure may trigger exacerbations of SLE, including the first symptoms that bring an individual to medical care

(Estadt et al., 2021; Harley and James, 2006). Environmental exposures that have most consistently been associated with risk of developing SLE are occupational exposure to respirable silica (Morotti et al., 2021), smoking history (Parisis et al., 2019), and vitamin D deficiency (Hassanalilou et al., 2017; Young et al., 2017). Viral infections and microbiomic factors may play a role in inducing or exacerbating SLE in susceptible persons (Quaglia et al., 2021). A recent meta-analysis of 33 studies found a significantly higher seropositivity for EBV antibodies in persons with SLE compared with controls (Li et al., 2019). Recent studies have also found associations between psychosocial trauma and depression with increased risk for developing SLE (Bookwalter et al., 2020; Roberts et al., 2017, 2020). The above environmental and psychosocial factors may contribute to epigenetic changes that modify expression of SLE-related genes, thereby leading to immune dysregulation (Ghodke-Puranik and Niewold, 2015).

Diagnostic Tools

The heterogeneous phenotypes, laboratory manifestations, and prognoses of SLE make diagnosis challenging. Disease severity for SLE ranges from trivial to lethal, and clinical presentations most often include arthritis, skin rashes, kidney disease, and blood disorders, though SLE can affect every organ in the body in any order at any time. SLE may present as an acute illness or it may take decades after first recognition of symptoms or abnormal laboratory tests to become clinically diagnosable (Arbuckle et al., 2003). Patients with nephritis only, rash only, or hematological manifestations only—and sharing no other clinical features—can all be said to have SLE. Some patients present with specific manifestations, such as seizure or renal failure, while others first develop a symptomatic problem a decade or more after first being diagnosed. Though trigger factors that induce flares, such as infection, sunlight exposure, allergic reactions, may play a role in a few individual patients, the timing of manifestations in most patients is not understood.

Autoantibodies are the most consistent laboratory feature of SLE. Most people with the condition have high titer antinuclear antibody, but antinuclear antibody is commonly found in other autoimmune diseases, such as Hashimoto’s thyroiditis, Sjögren’s disease, and scleroderma, as well as in otherwise normal people on occasion (Wallace and Gladman, 2019). Anti-DNA antibody and anti-Smith antibody, when present at high titer in symptomatic individuals, are diagnostic of SLE. In asymptomatic individuals, these autoantibodies suggest but do not predict future clinically evident SLE (Wallace and Gladman, 2019). Other autoantibodies, including anti-ribonuclear protein, anti-SSA/Ro, and anti-SSB/La are

commonly seen in people with SLE but are not diagnostic and instead may suggest concomitant Sjögren’s disease or mixed connective tissue disease (Pisetsky, 2020). Individuals with SLE usually have abnormal markers of inflammation, including erythrocyte sedimentation rate, C-reactive protein, and complement activation, and about half of those with SLE have proteinuria. When clinically indicated, skin, kidney, and other biopsies provide definitive diagnostic information (Wallace and Gladman, 2019).

Investigators have developed classification criteria for SLE for research purposes as a potential means of identifying relatively homogeneous groups of patients for inclusion in studies and trials. In 1982 and again in 1997, the American College of Rheumatology (ACR) published SLE classification criteria (Hochberg, 1997; Tan et al., 1982). The 2012 Systemic Lupus International Collaborating Clinics classification criteria (Petri et al., 2012) updated the ACR criteria to refine the SLE definition, include additional clinical and lab criteria, and emphasize SLE as primarily an autoantibody driven disease. These criteria are not limited to research purposes (Fava and Petri, 2019). Most recently, the 2019 European Alliance of Associations for Rheumatology² and ACR Rheumatology revised SLE classification criteria for research (Aringer et al., 2019; Fava and Petri, 2019), now requiring antinuclear antibody as an entry criterion for clinical trials, along with a weighted and additive scoring system for other criteria. While these classification schema are useful for clinical guidance, being specific but not sensitive, they are most appropriate for use in research rather than clinical diagnosis and management.

Treatments and Prospects for Cures

Most clinical and basic research studies of SLE involve patients who fulfill classification criteria, excluding almost half of patients who are considered by their physicians to have SLE but who do not fulfill these criteria (Jia et al., 2017; Lockshin et al., 2015, 2019). Specific severity, organ system involvement, and duration-related details dictate treatment, the latter focusing on accrued damage from either illness or its treatment. A number of entities have developed general treatment guidance. Some treatment recommendations, mostly based on systematic literature review, are provided by national and international rheumatology societies such as the ACR and the European Alliance of Associations for Rheumatology (Fanouriakis et al., 2019). Other recommendations are expert opinions that are not necessarily sponsored by organizations (Durcan et al., 2019). More specific treatment protocols exist for subsets of people with SLE, such as those with International Society of Nephrology/Renal Pathology Society

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² Formerly the European League Against Rheumatism.

(ISN/RPS) class IV lupus nephritis. Periodic treatment changes are common. Approximately one-third of SLE patients discontinue hydroxychloroquine—a first line of treatment—because they experience remission or find the medications ineffective (Mehat et al., 2017).

Standard therapies include hydroxychloroquine (the toxicity of which is related to lifetime dose), topical and systemic corticosteroids, and small molecule immunosuppressants such as mycophenolate mofetil, azathioprine, and cyclophosphamide (Durcan et al., 2019; Fava and Petri, 2019). In 2011, FDA approved belimumab, a B cell-depleting agent that has a shorter duration and less-toxic effect than rituximab, for SLE treatment in adults—the first drug approved for SLE in over 50 years. Indications were expanded to include pediatric patients in 2019 and SLE nephritis in 2020. FDA also approved voclosporin, an oral calcineurin inhibitor, in 2021 for the treatment of lupus nephritis, a manifestation of SLE in adults (FDA, 2021a; Rovin et al., 2021). Cytokine inhibitors targeted to type 1 interferon, such as anifrolumab, reduce disease activity (Morand et al., 2020). Anifrolumab was approved for use in SLE in 2021 (FDA, 2021c).

Because uncontrolled immune response, usually expressed by autoantibodies, is the likely cause of SLE symptoms, studies are focusing on monoclonal antibodies to block specific cellular and molecular pathways thought to be abnormal in SLE. Targets of therapies in ongoing clinical trials include B cells that synthesize autoantibodies (dapirolizumab, obinutuzumab) and T cells that instruct B cells as to what antibodies they should produce (itolizumab, ALPN-101). The interferon pathway is another clinical trial target (BIIB059). Other clinical trials are examining small molecule pharmaceuticals that block binding of antigen to cells (sirolimus) or mark immune and inflammatory cells for destruction (KPG-818) and IL-18 blockers for example.

Morbidity and mortality can result from kidney failure, heart failure, stroke, or infection during immunosuppressive therapy (Murimi-Worstell et al., 2020; Wallace and Gladman, 2019). Additional causes of disability include destructive arthritis, osteonecrosis, osteoporosis, and dementia (Lin et al., 2016; Wallace and Gladman, 2019). There is no known approach for preventing SLE, but long-term studies may be able identify trigger factors for transition from autoantibody-positive but asymptomatic disease to symptomatic disease or triggers for flares in clinically quiescent patients.

Animal Models

Animal models for SLE have existed for more than four decades (Richard and Gilkeson, 2018). While illustrative of specific mechanisms of illness, such as glomerulonephritis, none can completely reproduce

human SLE. Existing mouse models differ from human SLE in predictability of onset, sex distribution, absence of flares, and remissions, and they are limited for the most part to modeling specific manifestations such as nephritis, dermatitis, or arthritis (Moore et al., 2021; Richard and Gilkeson, 2018). These models do provide hypothesis-testing opportunities when assessing whether specific immune pathways are involved in the disease, and they can find use in testing new potential therapies in early preclinical studies.

Research Progress and Gaps

Major research progress in SLE consists of understanding—and targeting treatment to—molecular mechanisms that contribute to specific, if limited, forms of the illness (Barrat et al., 2019; Chen et al., 2021). Progress in understanding SLE will require research that leads to a better understanding of the basis of heterogeneity, change over time, epidemiology, and the relationship between phenotypic heterogeneity and disease progression. For instance, despite extensive genetic, epigenetic, and environmental data, questions remain as to why SLE affects mostly women, more non-White people, and mostly young persons; why SLE flares and remits; and why in some people SLE targets the kidneys, and in others the skin, joints, or blood (Lockshin, 2007). Research to identify the circumstances that trigger transition from autoantibody-positive to clinical SLE, or the triggers for flares in clinically quiescent people with the disease could lead to prevention and early intervention or treatment. In areas such as neuropsychiatric SLE (NPSLE) advances in biomarkers and disease models are needed. There is an unmet need for diagnostic biomarkers and innovation in imaging modalities for NPSLE (Kivity et al., 2015). Although some autoantibodies have been suggested as a potential biomarker, only a few antibodies have met the exploratory criteria and are being used in the diagnosis and therapeutic decisions (Govoni and Hanly, 2020; Sarwar et al., 2021). In addition to biomarkers, attention to models is also critical as in the case of neuropsychiatric manifestations of SLE (Karnopp et al., 2021).

Additionally, more research is needed to identify risk factors, including environmental and psychosocial factors that contribute to disease initiation. Over the past few years, however, investigators have made advances in understanding the pathophysiologic mechanisms underlying the heterogeneity of SLE, guiding drug development and leading to some successful clinical trials and FDA drug approval as noted above. Gaining a better understanding of the mechanisms triggering onset of SLE and those contributing to disease activity over time requires conducting additional longitudinal studies, collecting epidemiologic data, and using

life-course methodologies. In the interim, developing more sensitive classification schema for clinical diagnosis and disease management could improve the care of persons who may have SLE but who, under current guidelines, do not receive a diagnosis or treatment for the disease.

ANTIPHOSPHOLIPID SYNDROME

Antiphospholipid syndrome (APS), which was initially thought to be a subset of SLE but was defined as a separate syndrome in 1989 (Lockshin and Harris, 2017), has three manifestations. Thrombotic APS occurs in episodes, often triggered by an infection or a change in therapy, and is characterized by recurrent thromboses, heart valve disease, and a type of microangiopathic kidney involvement that differs from that seen with SLE. Long-term outcomes for thrombotic APS depend on the extent and location of thromboses; for example, one case could lead to deep vein thrombosis and another to stroke.

Obstetric APS is characterized by recurrent pregnancy complications including fetal growth restriction, fetal death, and severe preeclampsia. Most women with obstetric APS do not have thrombotic APS, and women with thrombotic APS do not necessarily develop obstetric APS (Garcia and Erkan, 2018; Simioni, 2012). However, women with APS who have suffered preeclampsia are at increased risk for cardiovascular events later in life (Simard et al., 2021).

Catastrophic APS (CAPS), a highly lethal form of the disease, affects less than 1 percent of those with APS (Cervera, 2017; Cervera and Group, 2010). In CAPS, severe, often lethal multi-organ thromboses occur over short periods of time (Garcia and Erkan, 2018).

Epidemiology and Impact

Information on disparities in the epidemiology of APS can be found in Box 3-3.

Complications, Other Morbidity, and Long-Term Consequences

Coexisting disease, overlap syndromes, progressive damage, and the adverse effects of treatment complicate APS. For example, in one small study, 33 percent of patients with APS had concomitant autoimmune disease, and over half of those had concomitant SLE (Abu-Zeinah et al., 2019). Women with obstetrical APS may have increased risk of hypertension and renal failure (Garcia and Erkan, 2018), and individuals with thrombotic APS suffer long-term disabilities resulting from neurologic, cardiac, and renal injury. The presence of SLE, history of arterial thrombosis, and organ damage can adversely affect health-related quality of life for individuals with APS (Desnoyers et al., 2020). Pain, fatigue, concerns about family planning, and medication unpredictability can also take a toll on the mental health of individuals with APS (Chighizola et al., 2021; Desnoyers et al., 2020). Death can result from kidney, brain, or cardiopulmonary thromboses, including heart valve disease and thrombotic microangiopathy occurring either separately or concomitantly, as in CAPS.

Economic Impact

Data on the economic impact of APS are lacking. Direct costs of care delivery include frequent physician visits, emergency room visits, hospitalizations, anticoagulant medication, and laboratory costs for close medication monitoring. Studies have found that impaired work productivity adds to the indirect costs of APS (Chighizola et al., 2021). However, quantitative data for the direct and indirect costs of APS are not available.

Risk Factors and Etiology

Other than family history, research has not identified risk factors for APS. The frequent observation (Garcia and Erkan, 2018) that infections trigger transient antiphospholipid antibodies points to an environmental cause, perhaps characterized by an abnormal response to exposure. Many infections, including syphilis, leprosy, and COVID-19, induce antiphospholipid antibodies transiently, though it is not yet clear whether infection-induced antibodies are pathogenic (Asherson and Cervera, 2003b; Ribeiro et al., 2019; Talotta and Robertson, 2021). Antiphospholipid antibodies persist over long periods of time.

Research suggests a genetic susceptibility for APS but has yet to define what that susceptibility might be (Gavriș et al., 2021; Lopez-Pedrera et al., 2019). Immobility, infection, smoking, and withdrawal of anticoagulant medication each can trigger thrombotic episodes (Cundiff, 2008; Johns Hopkins Medicine, n.d.), and microbiomic or other environmental factors may trigger APS in susceptible persons (Martirosyan et al., 2019; Ruff et

al., 2019). Antiphospholipid antibody, specifically lupus inhibitor, and pre-existing renal dysfunction predispose women to obstetric complications. Between thrombotic or obstetric episodes, people with APS do not have abnormal markers of inflammation and are mostly asymptomatic, though a small proportion of those with APS have ongoing cutaneous vasculitis or thrombocytopenia. Withdrawal of therapeutic anticoagulation, infection, and trauma can trigger CAPS.

Diagnostic Tools

By definition, people with APS must have persistent moderate-to-high titer immunoglobulin G (IgG) and/or immunoglobulin M (IgM) anticardiolipin, anti-beta-2-glycoprotein I, or lupus inhibitor antibodies, primarily of IgG isotype. These antibodies are sensitive for APS but not specific; many individuals with these antibodies are healthy or have alternate explanations for their presence (Gkrouzman et al., 2021; Misasi et al., 2015).

A classification criteria diagnosis of APS requires both a compatible clinical event such as pregnancy loss or thrombosis, and because infection-induced antibodies are usually transient, persistent high-titer anticardiolipin, anti-beta-2-glycoprotein I, or lupus inhibitor antibodies. Research has found other related autoantibodies that have not yet received official endorsement as biomarkers for APS, primarily because worldwide standards are not yet available. Individuals who do not meet criteria can nonetheless receive an APS diagnosis if they show atypical features, such as livedo racemosa, microvascular thrombosis, or Lib-man-Sacks endocarditis, together with positive serology. People who are acutely ill, specifically those with CAPS, can be diagnosed and treated without demonstrating that antibodies are persistent.

In patients with APS, a positive lupus inhibitor test has a high predictive value for pregnancy loss (Yelnik et al., 2016), and a global antiphospholipid syndrome score (GAPSS) has a high predictive value for thrombosis (Zuily et al., 2015).

Treatments and Prospects for Cures

Treatments for APS are based more on expert consensus than on clinical trial data and include aspirin, hydroxychloroquine, heparin and warfarin for acute thromboses, and heparin for pregnancies in women with prior pregnancy complications (Garcia and Erkan, 2018). Since most women with obstetric APS do not develop future thromboses, anticoagulation can be discontinued a few months postpartum. Treatment for thrombotic APS is usually lifelong anticoagulation with warfarin.

Hydroxychloroquine may improve outcomes in both thrombotic and obstetric APS (Garcia and Erkan, 2018; Sciascia et al., 2016). Although hydroxychloroquine may reduce the risk of thrombosis in patients with SLE, its efficacy is not yet proven for patients with APS who do not have SLE (Garcia and Erkan, 2018). Based on small prospective studies, individuals with atypical features such as leg ulcers, endocarditis, or neurologic or renal disease may benefit from use of rituximab (Garcia and Erkan, 2018). Researchers are also investigating anticomplement therapies such as eculizumab and endothelial protective therapy with statins (Garcia and Erkan, 2018). Antiphospholipid antibodies disappear over years in some people with APS, suggesting the possibility of withdrawal of anticoagulation for some patients. Research suggests that direct oral anticoagulants may be useful in the treatment of some mild and/or atypical APS patients, that is, those without thromboses or pregnancy losses. Direct oral anticoagulants are not recommended for higher risk APS patients, that is, patients who are pregnant; have histories of arterial or small vessel thromboses; or have triple positive antiphospholipid antibodies (lupus anticoagulant, aCL, and anti-ß2GPI antibodies) (Dufrost et al., 2020).

Animal Models

No spontaneous animal models of APS exist. Passively acquired antiphospholipid antibodies cause pregnancy loss and induce thrombosis; similarly in vitro studies on platelets, endothelial cells, and leukocytes suggest that autoimmune antiphospholipid antibodies are not secondary events but are directly pathogenic (Gandhi et al., 2021). There is no available infection-induced animal model of APS (Asherson and Cervera, 2003a; Garcia and Erkan, 2018). Discovery of such models would improve understanding of APS mechanisms.

Research Progress and Gaps

Epidemiologic data for APS are unavailable. Research has not identified the circumstances that trigger transition from autoantibody negative to positive or antibody positive to clinical APS, nor has it identified the triggers for flares in people who are clinically quiescent. Research gaps include the sources of the autoantibodies, evidence that the currently demonstrated autoantibodies are the primary actors, triggers for events, and the mechanisms by which the illnesses progresses. The interrelationship of APS with conditions such as NPSLE poses an additional level of complexity and challenges for research. Recent advances in epidemiology, genetics, and cell and cytokine biology promise progress in this area. Endothelial injury is a new area of exploration, especially since there

seem to be clear links between COVID-19 infection and the inflammatory and immunological injury seen in SLE and APS (Vlachoyiannopoulos et al., 2020; Winchester et al., 2021). Proposed treatment paradigms need confirmation with controlled clinical trials, and long-term prognosis data are needed. An international voluntary consortium (APS ACTION) is assembling worldwide data from clinics specializing in APS (Erkan et al., 2021). Additionally, quantitative data for the direct and indirect costs of APS are needed to determine the economic impact of the disease.

RHEUMATOID ARTHRITIS

Rheumatoid arthritis is a complex chronic disease characterized by joint inflammation, pain, swelling, and damage as well as by a variety of effects seen in the skin, lung and cardiovascular systems. Other generalized symptoms include fatigue and weight loss. Like many other autoimmune diseases, rheumatoid arthritis is characterized by periods of flares and remission, with long-term consequences including the systemic effects of the disease as well as complications from long-term drug therapies.

Epidemiology and Impact

Information on disparities in the epidemiology of rheumatoid arthritis can be found in Box 3-4.

Complications, Other Morbidity, and Long-Term Consequences

Complications and other conditions associated with rheumatoid arthritis stem in large part from the role that chronic inflammation plays in this disease. Chronic inflammation increases the risk of developing atherosclerosis, leading to strokes and myocardial infarction, and the risk of developing pulmonary fibrosis and interstitial lung disease (Kim and Suh, 2020; Lindhardsen et al., 2011). The chronic inflammation associated with rheumatoid arthritis can also damage the skin and eyes (Chua-Aguilera et al., 2017; Murray and Rauz, 2016). An increased risk of different types of lymphoma (Anderson et al., 2009) and of central or peripheral neurological system damage (Kaeley et al., 2019; Ramos-Remus et al., 2012) are also seen in people with rheumatoid arthritis. The results can be broad ranged. For example, significant morbidity, and in some cases, reduced life span, have been associated with central and peripheral neurological damage. Such damage may produce symptoms ranging from numbness in the hand to muscle weakness in all four limbs (quadripesis) as well as sudden death (Ramos-Remus et al., 2012).

Mortality resulting from cardiovascular and respiratory disease contribute to the increased overall mortality risk in people with rheumatoid arthritis (England et al., 2016; Yoshida et al., 2021). Studies have also found an increased risk of other autoimmune diseases, specifically type 1 diabetes, IBD, and thyroiditis, in people with rheumatoid arthritis, as well as an inverse association between rheumatoid arthritis and multiple

sclerosis (Somers et al., 2009). In addition, an individual may have a form of disease that shares features of both rheumatoid arthritis and SLE, also known as “rhupus”(Antonini et al., 2020; Jia et al., 2017; Lockshin et al., 2015), or one that shares features with Sjögren’s disease (Zhang et al., 2020). The long-term use of immune-suppressing medications increases the risk of infections (Kim and Suh, 2020).

The impact of rheumatoid arthritis on quality of life can be significant. For example, depression is common and is a key component that disease management should address (Matcham et al., 2013).

Economic Impact

The economic impact of rheumatoid arthritis is significant. One comprehensive analysis estimated a total cost of $47.6 billion (in 2005 dollars), based on estimates of direct health care costs ($8.4 billion), indirect costs of lost wages productivity, job turnover, and required household help ($19.3 billion), intangible costs relating to quality-of-life changes ($10.3 billion), and premature mortality ($9.6 billion) (Birnbaum et al., 2010).

The measurement of indirect costs is important given a decreasing trend in inpatient costs; this was due to improvement of clinical outcomes by biologic and targeted synthetic disease-modifying antirheumatic drugs. A decreasing trend in inpatient costs chronologically suggested a cost shift in other components of direct costs. Indirect costs still contributed a considerable proportion of total costs, with work disability being the main cost component. Economic analyses that do not incorporate or appropriately measure indirect costs will underestimate the full economic impact of rheumatoid arthritis (Hsieh et al., 2020).

A retrospective study of employed individuals (18–65) using 1996–2006 US Medical Expenditure Panel Survey data estimated national indirect costs of rheumatoid arthritis-related absenteeism as $252 million annually. The study concluded that there is a higher probability that individuals with rheumatoid arthritis will miss work and workdays than those without rheumatoid arthritis (Gunnarsson et al., 2015).

Risk Factors and Etiology

The autoantibodies seen most commonly in people with rheumatoid arthritis are rheumatoid factor and anti-citrullinated protein/peptide antibodies (van Delft and Huizinga, 2020). In synovial fluid, these autoantibodies may contribute to activation of the inflammatory immune response and the resulting tissue damage.

One of the most well-established risk factors for rheumatoid arthritis is cigarette smoking (Liu et al., 2019). This elevated risk, seen most

strongly and consistently in people with anti-citrullinated protein/peptide antibodies, exhibits a positive dose–response with duration and amount smoked in pack-years. Smoking cessation can delay or prevent development of rheumatoid arthritis. Studies have elucidated the interaction between smoking and the HLA-DR shared haplotype specific gene and the mechanisms through which smoking-mediated immune responses in the lung lead to autoantibody formation and immune activation, and ultimately damage and destruction of joints and other tissues (Stolt et al., 2010). This research has produced important insights into the systemic effects that can be produced by the immune responses to respiratory exposures in the lung (Catrina et al., 2014).

Research has also identified similar mechanisms with other respirable exposures, including silica and asbestos (Klareskog et al., 2020). Investigators have examined occupational silica exposure in numerous studies and found a strong and robust association and evidence of dose–response with various measures of increasing exposure. A 2020 meta-analysis of data from 15 studies found that the overall odds ratio for occupational silica exposure and risk of rheumatoid arthritis was 2.59 (Mehri et al., 2020). This analysis did not include the most recent study (Boudigaard et al., 2021) or several early studies (Brown et al., 1997; Rosenman et al., 1999), each of which provide additional support for the overall strength of the evidence. Silica induces apoptosis of macrophages, exposing intracellular self-antigens to a dysregulated immune response that involves increased production of proinflammatory cytokines, B-cell activation, and increased production of autoantibodies (Cooper et al., 2008).

Multiple studies have examined three risk factors—breastfeeding, alcohol consumption, and obesity—and yielded relatively robust and consistent findings. Breastfeeding appears to be a protective factor, as there is an inverse, dose-dependent association between women who have breastfed and rheumatoid arthritis, with a greater protective effect seen with a longer length of lactation (Chen et al., 2015). In a meta-analysis of six studies, the combined odds ratio was 0.68 for ever breastfeeding, 0.78 for 1 to 12 months of breastfeeding, and 0.58 for more than 12 months of breastfeeding versus never breastfeeding (Chen et al., 2015). Alcohol consumption and rheumatoid arthritis also shows an inverse association, with dose–response following a U-shaped curve (Maxwell et al., 2010; Scott et al., 2013). Higher body mass index is associated with an increasing risk of rheumatoid arthritis, with an estimated odds ratio of 1.15 and 1.31 for the overweight and obese categories, respectively (Qin et al., 2015).

Proinflammatory dietary factors, such as red meat and sugar-sweetened beverages, are associated with increased risk of rheumatoid arthritis, whereas anti-inflammatory diets, fish, and omega-3 fatty acid supplements

are associated with decreased risk of rheumatoid arthritis autoimmunity and rheumatoid arthritis, although not consistently (Benito-Garcia et al., 2007; Di Giuseppe et al., 2014a,b; Gan et al., 2016; Hu et al., 2014, 2017; Pattison et al., 2004; Sparks et al., 2019a,b).

The findings from studies of oral contraceptive use are mixed (Qi et al., 2014). Studies of infectious agents are few in number, but work examining Porphyromonas gingivalis, a bacteria associated with periodontitis, provides insights into possible mechanisms relating to production of anti-citrullinated protein/peptide antibodies (Klareskog et al., 2020). EBV has also been associated with development of rheumatoid arthritis. Persons with rheumatoid arthritis have high titers of EBV antibodies and high levels of EBV-infected B cells, which indicate the control of EBV infection is impeded (Balandraud and Roudier, 2018).

Studies examining the development of autoantibodies prior to development of symptomatic disease have advanced the understanding of the etiology of rheumatoid arthritis. Research conducted over the past 20 years has included multiple isotypes of rheumatoid factor and anti-citrullinated protein/peptide antibodies (Deane and Holers, 2021). Using blood banks and other sources of stored sera, retrospective and prospective studies have demonstrated the presence of these autoantibodies five or more years before clinical presentation of disease (Nielen et al., 2004). The highest positive predictive values occur with the presence of two or more autoantibodies (Deane and Holers, 2021). These observations provide the opportunity to develop strategies to prevent the progression from a preclinical to symptomatic disease. At a population level, reducing occupational exposure to respirable silica and discouraging smoking are two steps that could reduce the incidence of rheumatoid arthritis. Additional research is needed to determine whether the permissible exposure limits designed to reduce the risk of silicosis will also provide protection for rheumatoid arthritis and other systemic autoimmune diseases.

Diagnostic Tools

Many symptoms of early rheumatoid arthritis, such as fatigue and low-grade fever, are nonspecific. The presence of swelling and stiffness in multiple joints is characteristic of the disease, and testing for rheumatoid factor, anti-citrullinated protein/peptide antibodies, and measures of inflammation, including C-reactive protein and erythrocyte sedimentation rate, are a cornerstone of classification criteria (Aletaha et al., 2010).

Treatments and Prospects for Cures

Maximizing the length of remission periods and decreasing therapy side effects and complications, rather than achieving a cure, are the basis for therapeutic advances. Treatment of rheumatoid arthritis is aimed at reducing symptoms, improving function and quality of life, and preventing progression and damage to the affected areas and other long-term complications. Individuals with rheumatoid arthritis can reduce their medications when they achieve sustained improvements in disease activity. Treatment options include general nonsteroidal anti-inflammatory drugs, and immune-suppressant disease-modifying anti-rheumatic drugs. The latter group includes conventional or traditional agents such as methotrexate and leflunomide, biologics such as tumor necrosis factor (TNF) inhibitors and rituximab, and Janus kinase inhibitors targeted at specific immune pathways. Multiple organizations, including the ACR and the European Alliance of Associations for Rheumatology, have established and updated treatment guidelines (Crofford, 2013; Fraenkel et al., 2021; Singh et al., 2016; Smolen et al., 2020).

Animal Models

Researchers have developed numerous animal models, primarily in mice and rats, that demonstrate rheumatoid arthritis features including synovial hyperplasia, cartilage damage, bone erosion, and increased production of key proinflammatory cytokines involved in this disease, such as TNFα, interferons, and several interleukins (Choudhary et al., 2018). Researchers developing one of the earliest models in the 1940s used complete Freund’s adjuvant, a mixture of mineral oils, heat-killed mycobacteria, and emulsifying agent. Collagen is another common inducing agent, either with complete or incomplete Freund’s adjuvant, which omits mycobacterium. The choice of inducing agent, adjuvant, strain, and species enables investigators to examine different mechanisms, stages, and features of the disease. Mice expressing the human TNF gene (Keffer et al., 1991), and more recently, transgenic and knockout mouse models such as K/BxN mice (Monach et al., 2008) enable examination of the role of specific genes in inflammatory response.

Research Progress and Gaps

Important developments in rheumatoid arthritis over the past 30 years include understanding the heterogeneity of the disease and the usefulness of developing classification criteria to reflect the variability in phenotypes and biomarkers. In addition, researchers have made

considerable progress in developing a wider variety of treatment options based on specific immune pathways, coexisting illness, and individual patient preferences.

Questions pertaining to the development of the disease offer opportunities for research that could lead to prevention and earlier interventions. Studies examining the transition from an asymptomatic preclinical state in which rheumatoid arthritis-specific autoantibodies are present to symptomatic disease are needed. These studies would enable investigation of various environmental factors, and gene–environment interactions, associated with the development of subsets of disease defined by serology. It is also important to understand the role of these factors and interactions in disease progression and development of flares. The role of respiratory exposures and links between immune response in the lung to inflammation and pathology induced in other tissues is another promising avenue of research. Epidemiologically, the signal of recent temporal increases in incidence after years of apparent declines stresses the importance of elucidating environmental and modifiable risk factors and the need for continued public health surveillance for rheumatoid arthritis.

PSORIASIS

Psoriasis is an immune-mediated systemic inflammatory disease that manifests as chronic inflammatory effects in skin and joints (Reich, 2012). Psoriasis can affect any area of the skin but most typically affects the extensor surfaces of the forearms and shins, the peri-anal, peri-umbilical and retro-auricular regions, and the scalp (Boehncke and Schön, 2015), with up to 80 percent of people having scalp involvement (Ortonne et al., 2009). Multiple variants of psoriasis exist, including plaque psoriasis, guttate psoriasis, erythrodermic psoriasis, and pustular psoriasis. Chronic plaque psoriasis, also known as psoriasis vulgaris, accounts for 90 percent of psoriasis cases. Lesions are typified by sharply demarcated erythematous plaques that are covered by plates, or lamella, of silvery scales. The plaques can be few in number or can extend across large areas of the body. Erythroderma is a severe form of psoriasis that covers the entire body and can be life-threatening as a result of electrolyte disturbances and shedding of the outer layer of skin, known as desquamation, that can occur (Armstrong and Read, 2020; Boehncke and Schön, 2015).

Epidemiology and Impact

Information on disparities in the epidemiology of psoriasis disease can be found in Box 3-5.

Complications, Other Morbidity, and Long-Term Consequences

Psoriatic arthritis is a common co-occurring autoimmune disease with psoriasis. An estimated 5 to 40 percent of those with psoriasis develop psoriatic arthritis—characterized by stiffness, pain, and swelling of joints that can eventually lead to debilitating joint destruction—at some point in their lives (Henes et al., 2014; Mease and Goffe, 2005). Psoriasis either precedes or occurs at the same time as psoriatic arthritis in 85 percent of those with psoriasis (Armstrong and Read, 2020).

People with psoriasis, particularly its severe forms, have increased risk of developing cardiometabolic health conditions including type 2 diabetes, metabolic syndrome, coronary artery disease, and stroke (Armstrong et al., 2015; Armstrong and Read, 2020). Likely owing to sharing genetic susceptibility loci on chromosome 16q with Crohn’s disease, people with psoriasis have a four times greater prevalence of autoimmune IBD, including Crohn’s disease and ulcerative colitis, than the general population (Eppinga et al., 2017; Karason et al., 2003).

Several studies have documented linkages between psoriasis and depression, anxiety, and suicidal ideation (Dalgard et al., 2015; Dowlatshahi et al., 2014; Singh et al., 2017). Psoriasis has a significant physical

and psychological effect, similar to that of other skin lesions, and with a comparable effect on quality of life as hypertension, type 2 diabetes, or depression (Rapp et al., 1999). People with psoriasis may experience pain, itchy skin, and bleeding, and may experience stigma from others (Kimball et al., 2005).

Economic Impact

A 2015 study estimated the total cost of psoriasis in the United States to be $35.2 billion, with 35 percent, 34 percent, and 32 percent of the costs attributed to direct health care costs, reduced health-related quality of life, and decreased work-related productivity losses, respectively (Vanderpuye-Orgle et al., 2015).

Risk Factors and Etiology

Dysregulated interactions between innate and adaptive components of the immune system with cutaneous cells cause the skin lesions characteristic of psoriasis (Boehncke and Schön, 2015), though little is known about antibodies or antigens involved in the disease. Genetic, environmental, and behavioral factors have been implicated in the etiology of psoriasis, with genetic factors having the largest contribution to psoriasis development (Griffiths et al., 2021; Tsoi et al., 2017). In fact, research in the early 1970s first identified a higher incidence of psoriasis in first- and second-degree relatives of individuals who develop psoriasis compared with the general public. In addition, identical twins are up to three times more likely to share a diagnosis of psoriasis than fraternal twins (Alshobaili et al., 2010; Farber and Nall, 1974).

Numerous studies have identified multiple genes and chromosomal regions that increase the risk of developing psoriasis (Tiilikainen et al., 1980; Tsoi et al., 2017). Research also suggests that genetic factors influence disease severity. Individuals with earlier onset psoriasis are more likely to have a family history of the disease and tend to experience a more severe disease course compared with those who develop psoriasis later in life (Henseler and Christophers, 1985). Research has yet to identify external triggers for psoriasis for most instances of the disease. For individuals with a family history of psoriasis, and thus a presumed genetic susceptibility, triggering factors may include trauma to or irritation of the skin, including scratching, piercing, and sunburn; infections, particularly streptococcal upper respiratory infections in children (Besgen et al., 2010; Rasmussen, 1986); cigarette smoking (Armstrong et al., 2015; Naldi, 2016); certain medications, including interferon, lithium, and antimalarials

(Armstrong and Read, 2020; Boehncke and Schön, 2015); and metabolic and psychological stress (Armstrong et al., 2015; Rigas et al., 2019).

Diagnostic Tools

Clinical findings and family history are the primary diagnostic indicators of psoriasis. Clinicians will conduct a full body exam, paying particular attention to the skin and nails, and rely on a scoring system, such as the Psoriasis Global Assessment scale, Psoriasis Area and Severity Index, or the Lattice System Physician’s Global Assessment instrument (Langley and Ellis, 2004), to diagnose psoriasis and assess its severity, though they may also order a skin biopsy for atypical presentations of the disease (Armstrong and Read, 2020). Confounding conditions can include other inflammatory, infectious, and neoplastic conditions such as atopic dermatitis, seborrheic dermatitis, pityriasis rosea, syphilis, and cutaneous T-cell lymphoma.

Treatments and Prospects for Cures

Treatment options for psoriasis are based on the severity of the disease and whether the individual also has psoriatic arthritis. Corticosteroids, vitamin D analogs, calcineurin inhibitors, keratolytics, and targeted phototherapy are common options for mild psoriasis affecting less than 3 to 5 percent of the body surface area (Armstrong and Read, 2020). A metaanalysis of published research found that corticosteroids combined with vitamin D₃ improves psoriasis of the scalp, but further research is needed to inform safety and long-term maintenance treatment (Mason et al., 2013). Recommended treatments for moderate to severe psoriasis include biologics and oral agents, including methotrexate, apremilast, acitretin, and cyclosporine, combined with phototherapy (Martin et al., 2019). While oral agents were previously the treatment of choice for plaque psoriasis, TNF inhibitors, IL-12/23 inhibitor, IL-17 inhibitors, and IL-23 inhibitors since have proven to be more effective treatments (Feldman, 2021). FDA has also approved biological agents such as these for treating psoriatic arthritis (Armstrong and Read, 2020). However, a large study of patients with psoriasis who were treated with systemic therapies found that those treated with biologics were at a significantly increased risk for serious infections, particularly skin and soft tissue infections, compared with patients not undergoing biologics therapy (Dobry et al., 2017). One recent study found that Black individuals were less likely to receive new therapies for psoriasis (Bell et al., 2020).

Animal Models

There are few animal models for studying the etiology of psoriasis. Developing new diagnostics and treatments for psoriasis would benefit from developing highly predictive animal models (Bocheńska et al., 2017).

Research Progress and Gaps

Over the past decade, there have been considerable advances in the understanding of the pathogenesis of psoriasis and in the treatment of its heterogeneous manifestations. In particular, biologics for the treatment of moderate to severe plaque psoriasis have been a significant therapeutic advancement. Remaining research gaps include a need for further understanding of the mechanistic links between psoriasis, other autoimmune diseases, and comorbid diseases (Boehncke and Schön, 2015). There exists a particular gap in the early identification of psoriatic arthritis. A deeper understanding of environmental triggers for psoriasis is also needed. Epidemiologic data across the life course in persons with psoriasis is limited, as is research addressing patient-centered personalized care for each individual living with the disease. Studies of the socioeconomic impact of psoriasis are also lacking (Boehncke and Schön, 2015). As noted above, developing better animal models could contribute to advances in psoriasis treatments.

INFLAMMATORY BOWEL DISEASE

Ulcerative colitis and Crohn’s disease are two forms of the chronic idiopathic inflammatory disorder of the gastrointestinal tract known as IBD. The main symptoms of ulcerative colitis, which damages the mucosal layer of the rectum and colon, are diarrhea, rectal bleeding, passage of mucus, crampy abdominal pain, and a feeling that a bowel movement is imminent even though the bowels are empty. In most cases, symptoms are present for weeks to months before an individual seeks medical attention, though acute cases can occur. The extent of the disease—how much of the colon is affected—correlates with the severity of these symptoms. Ulcerative colitis almost always involves the rectum and often extends proximally to involve additional areas of the colon (Rubin et al., 2019).

Crohn’s disease involves the entire thickness of the wall of any part of the gastrointestinal tract rather than just the mucosal layer of the colon and bowel, and it usually presents as acute or chronic bowel inflammation. Localized inflammation in the gastrointestinal tract and the formation of

fistula tracts that can lead to fibrosis and narrowing of the intestines are two main characteristics of Crohn’s disease. Population-based conducted in Norway and Minnesota suggest that “Crohn’s disease presents with ileal, ileocolonic, or colonic disease in roughly one-third of patients each, and that only a small minority of patients (6–14 percent) will have a change in disease location over time” (Lichtenstein et al., 2018).

The inflammatory process in Crohn’s disease proceeds along one of two pathways, one leading to a pattern of obstructive fibrosis, the other in a pattern of penetrating fistulas. The treatment and prognosis differs for each of these patterns. Crohn’s disease, unlike ulcerative colitis, rarely affects the rectum (Lichtenstein et al., 2018), although a third of cases involve the area around the anus. Most often Crohn’s disease is patchy—it skips areas in the diseased intestine, whereas ulcerative colitis affects continuous regions—and in rare cases, Crohn’s disease can involve the liver and pancreas (Fousekis et al., 2018; Lichtenstein et al., 2018).

Epidemiology and Impact

Information on disparities in the epidemiology of IBD can be found in Box 3-6.

Complications, Other Morbidity, and Long-Term Consequences

IBD can co-occur with other autoimmune diseases including primary biliary cholangitis and celiac disease (Koulentaki et al., 1999; Oxford et al., 2013). Complications include an increased risk of depression and anxiety (Byrne et al., 2017), cardiovascular disease, stroke, and maternal and fetal complications (Agrawal et al., 2021b; Card et al., 2021; Chen and Wang, 2021; Choi et al., 2019; Odufalu et al., 2021). There is an increased risk of colon cancer in individuals with Crohn’s disease or ulcerative colitis in whom one-third or more of the colon is involved (Friedman et al., 2001, 2008). With immunosuppressive treatment, there is an increased risk of lymphoma, melanoma, non-melanoma skin cancers, and infections (Chupin et al., 2020; Long et al., 2012; Mill and Lawrance, 2014).

Up to one-third of patients with IBD have at least one extraintestinal disease manifestation, which can include rheumatologic disorders, metabolic bone disorders, dermatologic disorders, and urologic disorders (Barberio et al., 2021; Rogler et al., 2021; Sange et al., 2021; Shah et al., 2021).

Economic Impact

One study has estimated the total lifetime cost of IBD, as well as the difference between the costs associated with patients with IBD versus matched controls, using the Truven Health MarketScan insurance claims database for the period 2008 to 2015³ (Lichtenstein et al., 2020). Compared with matched controls, patients with Crohn’s disease diagnosed at any age incurred $416,352 in additional costs. For those diagnosed from birth to age 11, the additional costs totaled over the lifetime averaged $707,111, and those diagnosed at age 70 or older incurred an average of $177,614 in additional costs over their lifetime. The average total lifetime cost for patients of all ages was $622,056–$273,056 for outpatient expenses, $164,298 for inpatient services, $163,722 in pharmacy billings, and $20,979 for emergency department visits.

Compared with matched controls, patients with ulcerative colitis diagnosed at any age incurred $230,102 in additional costs over their lifetimes. For those diagnosed from birth to age 11, the additional costs totaled over the lifetime averaged $369,955, and those diagnosed at age 70 or older incurred an average of $132,396 in additional costs over their lifetime. The average total lifetime cost for patients of all ages was $405,496–$163,670 for outpatient expenses, $123,190 for inpatient services, $105,142 in pharmacy billings, and $13,493 for emergency department visits. Taken together, individuals with IBD will incur a total of $875 billion in lifetime

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³ Adjusted to 2016 U.S. dollars.

costs, $498 billion for those with Crohn’s disease and $377 billion for those with ulcerative colitis.

Risk Factors and Etiology

Epidemiologic studies have identified a variety of potential risks factors for developing IBD. For example, infectious gastroenteritis increases the risk of developing IBD by two- to three-fold (Acheson and Truelove, 1961; Barclay et al., 2009; Klement et al., 2004; Ng et al., 2015). In general, research has found associations between increased risk of developing IBD and low intake of fiber (Ananthakrishnan et al., 2013; Hou et al., 2011) and high intake of sweetened beverages (Racine et al., 2016); animal proteins, particularly red and processed meat; total fats; and polyunsaturated fatty acids, including both omega-6 and omega-3 fatty acids (Hou et al., 2011; Jantchou et al., 2010; Lewis and Abreu, 2017). The risk of being diagnosed with IBD before the ages of 10 and 20 years is 3 times and 1.6 times higher, respectively, for individuals who experience an infection during the first year of life (Bernstein et al., 2019). Sleep disruption has been shown to increase both the incidence and relapse of IBD (Ballesio et al., 2021; Beilman et al., 2020). Other risk factors include use of nonsteroidal anti-inflammatory medications, urbanization, and environmental pollution. Breastfeeding appears to be a protective factor for IBD development in children, with a longer period of breastfeeding providing greater protection (Barclay et al., 2009; Klement et al., 2004; Ng et al., 2015). While smoking is associated with a decreased risk of ulcerative colitis irrespective of race or ethnicity, it is associated with an increased risk of Crohn’s disease in non-Jewish White smokers (Piovani et al., 2021).

Research suggests that IBD arises because of a dysregulated response to commensal microbes within the intestine, though it is also affected by a complex interplay of host genetic risk, aberrant immune responses, and environmental factors. The mucosal immune system is altered in IBD and is characterized by an abundance of proinflammatory mediators from cells associated with adaptive immunity, such as T helper cells, and innate immunity, including macrophages and dendritic cells, which occur in increased numbers in mucosa affected by IBD. There is evidence that non-immune cells, such as epithelial and stromal cells, are also reprogrammed in IBD and play a significant role in the propagation of dysregulated immune responses. Historic paradigms regarding differential T helper cell responses in Crohn’s disease versus ulcerative colitis have evolved with the use of large-scale and multidimensional immunophenotyping of human tissue. The diseases seem to share many common immunological features (Chang, 2020; Mitsialis et al., 2020; Peterson and Artis, 2014).

As mentioned above, a number of rare single genetic mutations have been identified as the basis of susceptibility in up to 10 percent of cases of infantile IBD or very-early-onset IBD, suggesting a simple monogenic origin of the disease in these cases (Ouahed, 2021). More than 60 different gene defects have been identified in patients with very-early-onset IBD by whole exome sequencing. However, IBD in the majority of pediatric and adult patients involve the interplay of multiple genes with other factors (Nambu et al., 2021).

Diagnostic Tools

Clinicians use several diagnostic tools to assess disease activity and extent in IBD, including sigmoidoscopy before deciding the course of treatment for ulcerative colitis, and colonoscopy to determine the extent of disease in patients who are not having an acute flare (Pabla and Schwartz, 2020). Histology can provide information to grade activity in ulcerative colitis, though histologic features change more slowly than clinical features. There are also a number of abnormalities in Crohn’s disease that show up in laboratory tests, including levels of erythrocyte sedimentation rate and C-reactive protein, as well as hypoalbuminemia, anemia, and leukocytosis in more severe cases (Cappello and Morreale, 2016). Levels of the fecal proteins calprotectin and lactoferrin can distinguish IBD from irritable bowel syndrome,⁴ determine whether ulcerative colitis and Crohn’s disease are active, and detect whether Crohn’s disease has returned after surgery to remove the diseased portion of the intestines (Zhou et al., 2014). Studies have not found antibodies to be that useful in diagnosing IBD, though there is some evidence that increased levels of anti-Saccharomyces cerevisiae antibody may be indicative of Crohn’s disease and that elevated levels of perinuclear antineutrophil cytoplasmic antibody may occur more frequently in people with ulcerative colitis (Mitsuyama et al., 2016). However, antibody levels tend to be relatively insensitive to and nonspecific for IBD given that they are often elevated in other autoimmune diseases, infections, and inflammatory conditions, including those outside of the gastrointestinal tract (Kyriakidi et al., 2016; MedlinePlus, 2021; Roozendaal and Kallenberg, 1999).

Treatments and Prospects for Cures

Initial therapy for people with moderate to severe Crohn’s disease and ulcerative colitis usually includes biologic and small molecule

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⁴ Irritable bowel syndrome is the term for symptoms that occur when the contents of the large intestine move too quickly or too slowly.

therapy, with the goal of maintaining remission and preventing future complications. High-risk people with ulcerative colitis who are more likely to require biologics-based treatment include those with moderate to severe disease, steroid-dependent or steroid-refractory disease, and refractory inflammation of the ileoanal J pouch. High-risk people with Crohn’s disease who are more likely to require biologics include those who are younger than 30 and have extensive disease, with perianal or severe rectal disease and/or deep ulcerations in the colon and stricturing or penetrating disease behavior. The current goal of IBD treatment is to treat early in the disease course, treat aggressively with top–down biologics therapy, check drug and drug metabolite levels, administer dual therapy with immunomodulators and biologics in appropriate patients, and aim for deep remission as assessed by endoscopy and histology. Studies have shown that biologic therapies produce marked improvements in clinical symptoms and allow patients with IBD to enjoy a better quality of life with less disability, as well as fewer hospitalizations and surgeries (Al-Bawardy et al., 2021; Armuzzi and Liguori, 2021; Singh et al., 2020).

Diet plays a significant role in shaping the gut microbiome, and one theory holds that dietary components interact with the microbiome and stimulate a mucosal immune response. In fact, active Crohn’s disease responds to exclusive enteral nutrition or bowel rest with total parenteral nutrition (TPN), which have been shown to be as effective as glucocorticoids in inducing remission but are not as effective for maintenance therapy. This lends further support to the theory that dietary antigens stimulate an immune response. In contrast with Crohn’s disease, elemental diets or TPN are not effective treatments for ulcerative colitis.

Dietary approaches as maintenance therapy in Crohn’s disease have been adapted largely from findings of epidemiologic studies; however, there is significant heterogeneity among research studies. The overall dietary approach is to maximize fiber intake, particularly from fruits and vegetables, and to limit consumption of higher-risk foods. There are several defined diets that generally adhere to these principles with some variation. These diets include the Mediterranean diet pattern, Specific Carbohydrate Diet, Semi-Vegetarian Diet, and IBD Anti-Inflammatory Diet. However, much work remains to understand how diet might affect disease risk and activity, research that may eventually lead to evidence-based nutrition guidelines.

Therapies targeting specific cytokines, such as TNF, IL-12, and IL-23, have revolutionized IBD treatment. Therapy targeting immune cell trafficking to intestinal tissue has proven successful in IBD and shows continued promise. However, the cumulative repertoire of therapies for IBD is limited and many people with the condition suffer with refractory disease.

Animal Models

There are four categories of animal models of intestinal inflammation—chemical, genetically engineered, cell transfer, and congenic—that researchers use to study how IBD develops and explore new therapeutic approaches (Bamias et al., 2017). Chemical models, which researchers create by using harsh chemical to damage the colon, provide insight into early repair mechanisms, but not for studying the inflammatory processes active in IBD. Creating genetic engineering models involves either deleting genes that control the production of one or more proteins they suspect play a role in disease development or introducing mutations that lead to overproduction of those proteins. Such models are useful for studying specific pathways in the inflammatory response, but not for studying the complex interaction of different pathways that characterize both a normal and abnormal immune response.

Cell transfer models involve injecting different subsets of T cells from a donor into specially bred mice that lack adaptive immunity and that have been kept in germ-free environments. Researchers use cell transfer molecules to study the protective or pathogenic roles that specific types of T cells play in mucosal immunity, but because the animals are immunodeficient, unlike humans with IBD, the insights gained from these studies may not apply fully to IBD. Congenic models develop disease spontaneously as a result of specific breeding, genetic, or housing backgrounds. These models most closely recapitulate human disease, but they are hard to develop and the most complex to study. Efforts to develop safe and effective treatments for IBD could benefit from the development of additional animal models.

Research Progress and Gaps

Researchers have made progress in many areas of IBD, particularly in terms of developing effective biologic therapies and other therapeutic approaches for IBD. There has been progress in diagnosis such as using specialized MRI, computed tomography, video capsule technology, and colonoscopic evaluation. There have also been advances in identifying immunologic and environmental factors that may predispose an individual to developing IBD, as well as genetic factors involved in very-early-onset IBD.

Research gaps for IBD include the need to establish a more complete knowledge of disease etiology and pathogenesis and the influence of genetic predisposition and environmental factors on disease development and phenotype. Research is also needed to identify how to prevent onset of disease in a person with a strong familial risk. There is a large gap in

epidemiological data on IBD, including incidence and prevalence in the United States and well-designed studies that would provide a better picture of disease risk in the U.S. population.

Among the key needs are developing better biomarkers to monitor disease activity and determining the causes of disease flares and how to prevent them. Identifying the specific biological pathways that result in the observable characteristics and symptoms of IBD would enable matching effective medications to specific IBD manifestations. In addition, evaluating the efficacy of alternative and complementary therapies such as diet, stress-reduction, and nutritional supplements would represent an advance. Other useful research areas assess the safety of administering biologics and the thiopurine family of immunosuppressive drugs to individuals with IBD—during pregnancy in mothers and prior to conception in fathers—as well as determining the long-term health effects to the offspring (Kanis et al., 2017). Creating new animal models that define the safety and efficacy of novel therapeutic strategies for IBD could support advances in understanding of the disease.

CELIAC DISEASE

Chronic inflammation of the intestines, caused by the immune system’s reaction to dietary gluten, is the characteristic feature of celiac disease, sometimes called celiac sprue or gluten-sensitive enteropathy. Over time, this immune response destroys the intestinal mucosa, which hampers absorption of nutrients from the intestines and can cause diarrhea, fatigue, weight loss, bloating, constipation, and anemia. In children, malabsorption can affect growth and development (Lebwohl et al., 2018). In addition, the intestinal damage that arises in celiac disease can result in serious complications, described further below (Mayo Clinic, 2021a).

Epidemiology and Impact

Information on disparities in the epidemiology of celiac disease can be found in Box 3-7.

Complications, Other Morbidity, and Long-Term Consequences

Individuals with celiac disease typically have co-occurring autoimmune conditions such as type 1 diabetes, IBD, Hashimoto’s thyroiditis, Graves’ disease, primary biliary cholangitis, scleroderma, SLE, and dermatitis herpetiformis, an autoimmune blistering skin (Cohn et al., 2014; Fröhlich-Reiterer et al., 2008; Kahaly et al., 2018; Kurien et al., 2016; Lebwohl et al., 2021; Márquez and Martin, 2021; Pascual et al., 2014; Regev et al., 2021; Yang et al., 2005). When left untreated, celiac disease has significant associated morbidity, including anemia, folate and B12 deficiency, osteopenia and osteoporosis, gastrointestinal lymphoma, dental enamel defects, neurologic complications such as such as peripheral neuropathy and cerebellar ataxia, infertility, and growth retardation in children (Caio et al., 2019; Catassi et al., 2005; Green et al., 2003; Jericho et al., 2017; Kupfer and Jabri, 2012; Lebwohl et al., 2018; Leonard et al., 2017; Lundin and Wijmenga, 2015; Rubio-Tapia et al., 2013; Salem and Estephan, 2005; Therrien et al., 2020). In addition, persons with the disease are at an increased risk for pneumococcal infection, particularly if unvaccinated, as well as sepsis (Simons et al., 2018).

Depression and related mood disorders have been reported to be more common in patients with celiac disease compared to those without the disease (Jackson et al., 2012; Smith and Gerdes, 2012). Anxiety disorders are associated with gluten intolerance, and there are conflicting findings regarding whether a gluten-free diet decreases anxiety in patients with celiac disease (Jackson et al., 2012; Rostami-Nejad et al., 2020).

An uncommon complication is refractory celiac disease (Hujoel and Murray, 2020; Penny et al., 2020). Symptoms mimic those of severe untreated celiac disease; however, unlike celiac disease, there is no or,

at best, an incomplete response to dietary gluten withdrawal. The prognosis is uncertain for patients with refractory celiac disease, and many develop intractable nutritional deficiencies requiring long-term parenteral alimentation that may lead to complicating infections. The importance of diagnosing celiac disease-associated with these concomitant diseases is essential since a gluten-free diet is able to resolve symptoms and prevent the potentially severe long-term complications (Caio et al., 2019).

Economic Impact

One study of patients with celiac disease confirmed by endoscopic biopsy estimated all-cause health costs associated with this disease over the course of 2 years (Cappell et al., 2020). Compared with health care costs for individuals without celiac disease, the average all-cause health care costs for individuals with celiac disease were $15,687 versus $12,220 at time zero, $19,181 versus $11,260 after 1 year, and $15,355 versus $11,579 in year two. At the start of the study, all-cause inpatient admissions costs and outpatient services costs were higher for individuals with celiac disease than for controls, but outpatient pharmacy costs were similar between the two groups. Patients with celiac disease, compared with control subjects, spent a greater percentage of their total health care costs on outpatient services (64.5 percent versus 59.4 percent) but a smaller percentage on outpatient pharmacy expenses (16.6 percent versus 22.3 percent).

Risk Factors and Etiology

Celiac disease correlates strongly with specific variations in HLA genes, but that association does not fully account for the risk of developing the disease (Kuja-Halkola et al., 2016; Sciurti et al., 2018). Since almost everyone consumes dietary gluten during his or her lifetime, other environmental or other risk factors may trigger the body’s lost tolerance to dietary gluten and increase the risk of developing celiac disease. Exposures occurring in utero or very early in life may be important predisposing factors, as suggested by the observation that children born during the spring and summer are at the highest risk of developing celiac disease (Namatovu et al., 2016). Research has identified several promising risk factors, including gastrointestinal infections (Kemppainen et al., 2017; Lindfors et al., 2019; Stene et al., 2006) and high gluten intake in early childhood (Andrén Aronsson et al., 2019; Lindfors et al., 2019).

The development of celiac disease is complex, and multiple research studies are in progress to better understand the pathogenic process. One avenue of research is exploring the role that gliadins, key components of gluten, play in disease development. Gliadins are complex proteins that

are unusually rich in the amino acids proline and glutamine and that intestinal enzymes cannot break down completely. The final product of this partial digestion is a mix of peptides that can trigger host responses including increased gut permeability and innate and adaptive immune responses that closely resemble those instigated by the exposure to potentially harmful microorganisms (Caio et al., 2019).

Diagnostic Tools

Many cases of celiac disease occur with neither a family history nor its classical symptoms such as chronic diarrhea and weight loss (Agardh et al., 2015; Stahl et al., 2021). Noninvasive and more sensitive screening tools have revealed celiac disease to be a heterogeneous disease (Lad and Jacobson, 2001); in fact, nonspecific symptoms often go unrecognized by clinicians and the individuals with the condition, leading to diagnostic delay (Paez et al., 2017). One study from the Netherlands, for example, used antibody testing to screen a cohort of 6-year-old children for celiac disease. This study found that screening-identified subclinical and asymptomatic individuals had a lower body mass index and lower bone mineral density than their healthy peers (Jansen et al., 2015, 2018), suggesting that the disease process is occurring before symptoms are recognized and that it would be beneficial to screen more regularly for celiac disease using both the Enzyme-linked immunoassay (ELISA)-based anti-tissue transglutaminase (tTG) immunoglobulin A (IgA) and the immunofluorescent anti-endomysium (EmA) IgA tests (Baudon et al., 2004).

In the same way that the clinical manifestations of celiac disease can vary enormously, so too can laboratory findings. Patients with atypical celiac disease often have no abnormalities in their complete blood count and comprehensive panel or merely show evidence of iron or folate deficiencies, while those with more classical presentations of the disease can have multiple lab test abnormalities such as abnormal quantities of fat in stool samples and abnormally low blood levels of albumin, the blood-clotting protein thrombin, or calcium (Lebwohl et al., 2018; Loginov et al., 1984; Meena et al., 2020; Rickels and Mandel, 2004).

Serologic tests are useful screening tests for celiac disease. Both the anti-tTG IgA and anti-EmA IgA tests have reported sensitivities of 94 to 98 percent and specificities of 91 to 100 percent (Caio et al., 2019; Leffler and Schuppan, 2010), though the sensitivities of those assays are somewhat lower in infants, toddlers, and people with mild disease. Clinicians use the anti-tTG IgA test as the initial screening test owing to its higher sensitivity (98 percent versus 95 percent), while they use the operator-dependent and more costly anti-EmA IgA test when the anti-tTG IgA test is unexpectedly negative or to confirm a positive anti-tTG IgA test (Leffler

and Schuppan, 2010; Medical Advisory, 2010; NIDDK, 2021a). Unexpected false-negative results can occur among the 2 to 3 percent of people with celiac disease who also have an IgA deficiency, in which case there are less sensitive IgG-based assays that clinicians can use (Caio et al., 2019; Rubio-Tapia et al., 2013).

Recently, both anti-deamidated gliadin peptide (DGP) IgA and IgG antibody tests have become available, though there is no evidence that anti-DGP IgA testing provides a significant advantage over anti-tTG IgA testing. On the other hand, the anti-DGP IgG test has higher sensitivity (80.0 percent) and specificity (98.0 percent) than the anti-tTG IgG test and is the serological test of choice in IgA-deficient individuals (Leffler and Schuppan, 2010; Zucchini et al., 2016).

The gold standard for celiac diagnosis remains mucosal intestinal biopsy of the bulb, the distal duodenum, or proximal jejunum combined with a clinical response to eliminating gluten from the diet of an individual suspected to have celiac disease (Freeman, 2018). The one exception to this rule pertains to children and adolescents whose anti-tTG IgA levels exceed 10 times the upper limit of normal, who are also anti-EmA positive using a separate blood sample, and who test positive for two specific celiac-associated genes, HLA-DQ2 and/or HLA-DQ8 (Kelly et al., 2015). If these criteria are met in the pediatric population, new guidelines say that clinicians can skip the biopsy prior to starting the individual on a gluten-free diet.

Treatment and Prospects for Cures

Adhering to a gluten-free diet is standard treatment for this disease. Instead of eating products containing wheat, barley, rye, and triticale, individuals can turn to products made from rice, corn, potatoes, millet, and soybeans. Individuals with celiac disease can tolerate moderate quantities of oats, but only brands that are certified as not contaminated with wheat and other cereal grains during processing and shipping (Green and Cellier, 2007; Husby et al., 2019; Ludvigsson et al., 2014; Rubio-Tapia et al., 2013). Individuals with celiac disease may also require iron and folate supplements if laboratory tests show deficiencies in these micronutrients, and they may require calcium and vitamin D supplements if bone density measurements reveal they have osteopenia (NIH Osteoporosis and Related Bone Diseases National Resource Center, 2018; Rondanelli et al., 2019). Other aspects of care for individuals with celiac disease should include pneumococcal vaccination, especially if there is evidence of decreased spleen function (Passanisi et al., 2020), and identification of other food intolerances (Rubio-Tapia et al., 2013). Clinicians should refer

individuals with celiac disease to a dietician familiar with this disease and to lay support groups to help them maintain gluten-free diets.

Clinicians should monitor dietary compliance every 6 to 12 months by ordering a repeat anti-tTG IgA or anti-EmA IgA test; these antibodies disappear when individuals comply fully with a gluten-free diet (Moreno et al., 2017). If symptoms do not recur, specific follow-up medical care is not necessary, aside perhaps from laboratory tests such as an annual hemoglobin or hematocrit test and bone density monitoring (Beyond Celiac, n.d.).

Research on preventing celiac disease has focused on manipulating the infant diet, based on observational studies suggesting that the timing of gluten introduction to the infant diet may affect the risk of developing the disease (Pinto-Sánchez et al., 2016). While one randomized controlled trial (RCT) in the general population found that infants who had gluten added to their diets at 4 months of age had a reduced prevalence of celiac disease compared with infants who were exclusively breastfed until 6 months of age (Logan et al., 2020), two larger RCTs in infants at risk for celiac disease found no significant effect of the timing of gluten introduction on incidence of celiac disease (Lionetti et al., 2014; Vriezinga et al., 2014).

Recently, investigators published the results of the first randomized trial of a transglutaminase 2 inhibitor (Schuppan et al., 2021). In this preliminary trial, treatment with this agent attenuated gluten-induced duodenal mucosal damage in patients with celiac disease.

Animal Models

Researchers have developed several useful animal models of celiac disease, although none fully captures all features of disease pathology. One group developed models of spontaneous gliadin-dependent intestinal inflammation in rhesus macaques and Irish setters that produce some of the hallmarks of celiac disease (Costes et al., 2015). Researchers have also seen spontaneous inflammatory small bowel disease in horses that resolves after 6 months of a gluten-free diet (van der Kolk et al., 2012). Investigators have used gluten sensitization to study gluten-dependent intestinal inflammation conditions in mice and rats. Some of the rodent models have been used to test the immunogenicity of detoxified gluten products, while others have proven valuable for studying adaptive immune responses to gluten. Recently, researchers have developed a mouse model that overexpresses interleukin-15 (IL-15) in the gut epithelium and thin layer of connective tissue that lies beneath the epithelial layer. This model mimics the immune system features and gluten-dependent intestinal damage seen in celiac disease and suggests that location-specific expression of IL-15 plays a central role in the development of

celiac disease. This new model may prove useful for generating new knowledge about the development of celiac disease and for testing new therapeutic strategies (Abadie et al., 2020).

Research Progress and Gaps

Celiac disease is unusual among autoimmune diseases in that research has identified the external trigger—dietary gluten—and the genetic background necessary for disease development. Even with this knowledge, though, there is currently no way to prevent the disease. Two prospective cohort studies have leveraged NIH funding and studied the genetic and environmental determinants of both type 1 diabetes and celiac disease: the Colorado-based Diabetes Autoimmunity Study in the Young, also known as DAISY,⁵ and the multicenter international study The Environmental Determinants of Diabetes in the Young, also known as TEDDY.⁶ In these cohorts, the investigators are monitoring autoantibodies associated with both type 1 diabetes and celiac disease frequently from birth, with a prompt referral for further medical evaluation of those testing positive. Follow-up of these cohorts is critical to understanding the life course of celiac disease and to offer clues as to how to prevent these diseases.

An additional research gap is that celiac disease remains under-diagnosed in the general population (Singh et al., 2018). Since some people have minimal symptoms, those diagnosed with celiac disease may represent the tip of iceberg. Thus, more research is needed to estimate the true incidence and prevalence in the population. Another major research gap is that there is currently no treatment for the gastrointestinal symptoms of a person with celiac disease who has inadvertently ingested gluten. The gluten-free diet is very restrictive and not all “gluten-free” labels are accurate. Inadvertent gluten ingestion can cause severe symptoms.

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⁵ The Diabetes Autoimmunity Study in the Young (DAISY) is a prospective cohort study that enrolled 2,547 children with a high-risk HLA genotype (enrolled at birth) or a first-degree relative with type 1 diabetes (enrolled between birth and age 7 years) (Frohnert et al., 2017; NLM, 2021). The children have been monitored for over 20 years for development of type 1 diabetes-related autoimmunity.

⁶ The Environmental Determinants of Diabetes in the Young (TEDDY) study is a prospective observational multicenter cohort study to identify infectious agents, dietary factors, or other environmental exposures that are associated with increased risk of autoimmunity and type 1 diabetes (NIDDK, 2021b). The study has enrolled 8,676 newborns who are less than 4 months old with high-risk human leukocyte antigen alleles or who are first-degree relatives of patients affected with type 1 diabetes. The children are followed up for 15 years.

PRIMARY BILIARY CHOLANGITIS

PBC (previously called primary biliary cirrhosis) is an immune-mediated chronic disease that slowly destroys the bile ducts in the liver. Persons affected are commonly asymptomatic at presentation; however, they may experience fatigue or symptoms of cholestasis such as itching skin or fatty stool, or symptoms of cirrhosis such as hypertension of the portal vein leading to the liver, or ascites, fluid collecting in the abdomen that can be painful when severe (Civan, 2019; Mayo Clinic, 2021d). Individuals with PBC can develop cirrhosis and liver failure and may require liver transplantation.

Epidemiology and Impact

Information on disparities in the epidemiology of PBC can be found in Box 3-8.

Complications, Other Morbidity, and Long-Term Consequences

Individuals with PBC may experience severe, long-term consequences resulting from complications related to chronic reduction in bile flow, including osteoporosis, itchy skin, hyperlipidemia, fatigue, and sicca syndrome, one form of which is Sjögren’s disease. A deficiency of fat-soluble vitamins may occur in persons with PBC, particularly in those with advanced-stage disease. Vitamin A deficiency can also occur in up to one-third of those with the disease, and cases of night blindness have been reported (Phillips et al., 2001; Waqar et al., 2010). Complications related to cirrhosis include hepatocellular carcinoma and portal hypertension as well as susceptibility to a variety of infections (Bajaj et al., 2021). Clinicians normally refer patients with end-stage PBC for liver transplantation (Carey et al., 2015; Lindor et al., 2019).

Fatigue is a major complaint in individuals with PBC, affecting approximately 50 percent of those with the disease, and 20 percent are affected in significant or life-changing ways (Jopson and Jones, 2015). Self-reported anxiety and depression or depressive symptoms are also common (Sivakumar and Kowdley, 2021; Zenouzi et al., 2018), and a large population study found that depression and fatigue have a significant effect on perceived quality of life in persons with PBC (Mells et al., 2013).

Economic Impact

One study estimated the average all-cause cost of inpatient medical care for individuals with PBC to be $3,905 per patient per month (Primary biliary cholangitis: Patient characteristics and the health care economic burden in the United States, 2021), of which 66 percent, or an average of $2,577 per patient per month, was attributed to PBC. This study also estimated the average total cost for all health care for individuals with PBC to be $6,568 per patient per month.

Researchers have also examined the cost effectiveness of obeticholic acid (OCA) therapy (Samur et al., 2017) using a mathematical model to simulate the lifetime course for patients with PBC treated with OCA plus ursodeoxycholic acid (UDCA) versus UDCA alone. This analysis estimated that OCA plus UDCA could reduce severe disease over the course of 15 years. Cumulative incidence of decompensated cirrhosis would decrease from 12.2 percent of individuals treated with UDCA alone to 4.5 percent, hepatocellular carcinoma would decrease from 9.1 percent to 4.0 percent, and liver-related deaths would decrease from 16.2 percent to 5.7 percent. The need for liver transplants would decrease by nearly 75 percent, from 4.5 percent of individuals with PBC to 1.2 percent, and transplant-free survival would increase from 61.1 percent to 72.9 percent. While the lifetime cost of adding OCA to the treatment regimen would

increase from $63,000 to $902,000, the analysis estimated that the incremental cost-effectiveness ratio for the combination therapy would be $473,400 per quality-adjusted life year gained.

Risk Factors and Etiology

PBC develops through the combined effects of genetics, environment, and autoimmunity. A family history of PBC or of other autoimmune diseases and a history of smoking are among the risk factors for PBC (Smyk et al., 2012; Tanaka et al., 2018). The first-degree relatives of people with PBC have a 10-fold higher prevalence of disease than the general population, and PBC has the highest reported concordance rate (63 percent) in identical twins of any autoimmune disease (Webb et al., 2015). The prevalence of anti-mitochondrial autoantibodies, a biomarker for PBC, in the first-degree relatives of persons with PBC is 13.1 percent compared with 1 percent in controls (Lindor et al., 2019).

Research has identified several possible environmental triggers for PBC, including infectious agents and industrial pollutants that have significant homology with human mitochondrial proteins (Gershwin et al., 2005; Juran and Lazaridis, 2014). Other potential triggers include cosmetic products such as nail polish and lipsticks (Tanaka et al., 2018). Several studies have found an association between PBC and urinary tract infections caused by Escherichia coli (Koutsoumpas et al., 2014; Wang et al., 2014), while the evidence suggesting that environmental toxins may trigger PBC comes from geographical clustering of PBC cases around areas of toxic waste disposal and in low-income areas (Juran and Lazaridis, 2014). Exposure to these triggers may thus lead to the immune system losing self-tolerance against the homologous human proteins, which results in persistent T cell-mediated destruction of the intrahepatic bile ducts and injury from accumulating bile salts. Over time, this damage can lead to biliary cirrhosis and decompensated liver disease (Figure 3-1).

Older age and measures of poorer liver function at diagnosis are associated with a higher mortality risk from PBC (Lu et al., 2018), while histologic stage of the disease predicts survival. One study measuring the rate of histologic progression found that the average time for individuals with PBC to develop extensive fibrosis was 2 years, with only a 29 percent probability of stabilizing in early-stage PBC after 4 years. This study also found that 50 percent of the individuals who only had what is known as interface hepatitis without fibrosis developed cirrhosis within 4 years, and only 20 percent of the pre-cirrhotic individuals were histologically stable. The average rate of histologic stage progression was one stage every 1.5 years (Lindor et al., 2019).

Diagnostic Tools

PBC presents in a heterogeneous fashion; about 50 percent of people are asymptomatic at diagnosis (Khanna et al., 2018). In one population based study, approximately half of patients who were initially asymptomatic developed symptoms within 5 years of PBC diagnosis, and only 5 percent remained symptom free after 20 years (Prince et al., 2004). An incidental finding of elevated alkaline phosphate, abnormally low bile flow, or a positive test for anti-mitochondrial antibody after screening for autoimmune extrahepatic disease are the common ways in which clinicians initially identify individuals with PBC (Hirschfield, 2017; Lindor et al., 2019). Clinicians will confirm a PBC diagnosis when two of the following three criteria are met: assays suggesting that bile flow is reduced or absent, the presence of anti-mitochondrial antibodies, and histology results indicating inflammation of the interlobular bile ducts that does not involve pus formation. Elevated bilirubin levels suggest more advanced disease is present, and while aminotransferases can be elevated, the pattern of liver injury is predominantly related to reduced or absent bile flow (Hirschfield, 2017; Lindor et al., 2019).

Anti-mitochondrial antibodies are present in 90 to 95 percent of those diagnosed with PBC (Colapietro et al., 2021). The presence of this autoantibody, which is involved in T cell-mediated destruction of the bile ducts, precedes biochemically apparent liver injury by several years. Individuals with PBC may also test positive for antinuclear and other autoantibodies, though their diagnostic utility is limited because of poor sensitivity (de Liso et al., 2018).

Once there is biochemical evidence of reduced or absent bile flow—via an elevated level of alkaline phosphatase and often a concurrently elevated level of 5’-nucleotidase and gamma-glutamyl transpeptidase—clinicians order noninvasive imaging of the liver and biliary tree to rule out a biliary obstruction. Direct bilirubin is elevated in later stages of the disease. In the event of an unclear diagnosis, clinicians may pursue X-ray or MRI examination of the bile ducts; in some instances, it may be necessary to conduct an endoscopic evaluation of the bile ducts.

Noninvasive transient elastography, which measures liver stiffness, has proven to be highly accurate at diagnosing advanced fibrosis in individuals with PBC. Progressive liver stiffness in PBC is predictive of a poor outcome (Lindor et al., 2019). Liver stiffness increases markedly over a 5-year period in treated individuals with cirrhosis and PBC; in treated individuals without cirrhosis, however, stiffness usually remains stable (Lindor et al., 2019). One study found that individuals with a liver stiffness of greater than 9.6 kilopascals—the normal range is 2 to 6 kilopascals—were five times more likely to result in clinical decompensation, death, or liver transplantation (Corpechot et al., 2012).

Treatments and Prospects for Cures

UDCA is the first-line therapy for PBC (Poupon et al., 1997), and clinical trials have shown that UDCA therapy improves liver biochemistries, improves survival, and reduces the need for liver transplantation (Figure 3-2) (Carey et al., 2015; Lindor et al., 2019). Individuals with early-stage PBC typically respond better to UDCA than those with advanced disease; however, even in individuals with advanced disease, treatment with a UDCA dosage of 13–15 milligrams per kilogram of body weight per day may improve survival and eliminate the need for liver transplantation (Corpechot et al., 2000; Lindor et al., 1994; Poupon et al., 1994). UDCA therapy may also reduce serum low-density lipoprotein cholesterol levels and slow histologic progression (Corpechot et al., 2000; Poupon et al., 1993), but it does not improve fatigue, itchy skin, associated bone disease, or autoimmune features that can accompany PBC (Lindor et al., 2019).

Clinical guidelines state that clinicians should assess the biochemical response after 1 year of UDCA therapy, with liver biopsy being

uninformative (Lindor et al., 2019). Bilirubin level is strongest indicator of survival after treatment with UDCA, with alkaline phosphatase levels also being a predictor of survival (Hirschfield, 2017). Positive response to UDCA therapy is typically evident with a few weeks, with 90 percent of the improvement occurring in 6 to 9 months and 20 percent of those treated with UDCA having normalized liver biochemistries after 2 years of treatment (Lindor et al., 2019). Life expectancy for individuals whose bilirubin and alkaline phosphatase levels return to normal after treatment (Hirschfield, 2017; Hohenester et al., 2009).

In 2016, FDA approved OCA for individuals who cannot tolerate UDCA, and in combination with UDCA for the treatment of individuals who do not have an adequate response to UDCA alone after 1 year of treatment (Krupa et al., 2022). In September 2017, FDA issued a warning regarding the use of OCA in patients with moderate to severe liver impairment following reports that OCA was associated with worsening PBC and death (FDA, 2017b). In May 2021, FDA restricted the use of OCA in patients that have PBC with advanced cirrhosis of the liver due to the potential for serious harm, such as advanced liver decompensation or liver failure, that can be attributed to starting OCA (FDA, 2021b).

OCA modulates bile acid synthesis, absorption, transport, secretion, and metabolism with the net effect of increasing the flow of bile from the liver (FDA, 2018b; Hirschfield et al., 2015). There is some evidence from animal models that OCA might have antifibrotic and anti-inflammatory activity. While clinical trials assessing whether OCA has an effect on survival of individuals with PBC are in progress, simulation models suggest that combined UDCA and OCA therapy could decreases the 15-year cumulative incidences of decompensated cirrhosis, hepatocellular carcinoma, liver transplants, and liver-associated mortality (Samur et al., 2017).

Studies have shown that fibrates, medication prescribed to lower high triglyceride levels, can reduce bile acid synthesis and increase production of bile acid transporter molecules. As a result, studies have evaluated fibrates for treating PBC and found them to be effective for individuals who do not respond to UDCA (Corpechot et al., 2018; Honda et al., 2019; Iwasaki et al., 1999). Recent studies have shown fibrates to improve liver biochemistries and liver stiffness, in addition to increasing survival without liver transplantation (Corpechot et al., 2018; Honda et al., 2019).

Investigators have evaluated a number of other drugs, but none were effective as single agents, and those investigated in combination with UDCA did not yield greater benefit than UDCA alone (Lindor et al., 2019). More recently, researchers have been studying peroxisome proliferator activated receptor-alpha (PPAR-α) agonists and various antifibrotic agents as potential PBC therapies (Gerussi et al., 2020).

Animal Models

Investigators have developed a variety of animal models that recapitulate at least some of the clinical, histological, and immunological features of PBC These models include genetically modified spontaneous models, xenobiotic immunized models, and infection-triggered models. No single animal model, however, reflects the varied clinical course and complex immunology of PBC (Katsumi et al., 2015).

Research Progress and Gaps

The lack of effective medical therapies for treating PBC, and particularly for treating severe cases of itching skin in some individuals with PBC, represents a critical gap. Novel therapies continue to be investigated. Better genetic and immunology screening tests are needed to determine who is at elevated risk for developing PBC. Research on approaches to preventing histopathologic disease in those with positive serology is also required. New animal models that reflect the varied clinical course and complex immunology of PBC would be helpful. In addition, life-course studies that follow the patient through diagnosis, treatment, and disease sequelae, as well as incidence and prevalence studies that reflect the entire U.S. population, are needed.

MULTIPLE SCLEROSIS

Multiple sclerosis is an autoimmune disorder of the CNS that causes inflammation that damages the myelin sheath enveloping the axons of neurons. This inflammation can also eventually affect the nerve fibers themselves, causing them to degenerate. Demyelination, with or without nerve fiber degeneration, interrupts transmission of signals that control muscle function and bring sensation from organs and limbs in the body (Mayo Clinic, 2020a; Podbielska et al., 2013). Depending on the location of the damage in the brain and spinal cord, a wide range of neurologic symptoms and impairment can occur, including vision problems, numbness, tremor, lack of coordination, impaired balance, weakness, bowel and bladder problems, and inability to walk (Mayo Clinic, 2021c). In addition, fatigue is a common manifestation of multiple sclerosis and has been found to have a significant negative impact on patient-reported quality of life (Young et al., 2021).

Relapsing-remitting multiple sclerosis is the type of multiple sclerosis initially diagnosed among 85 percent of individuals with a new diagnosis of multiple sclerosis; it is characterized by episodes of neurological relapses followed by partial or complete neurologic recovery

(Goldenberg, 2012). In a majority of individuals, symptoms remit over a period of weeks to months. Prior to the development of disease-modifying therapies, about half of individuals with relapsing-remitting multiple sclerosis would transition to a second phase, called secondary progressive multiple sclerosis, within 10 years (National Multiple Sclerosis Society, n.d.-a). The course of secondary progressive multiple sclerosis is characterized by neurologic progression, with few or no episodes of relapse.

Primary progressive multiple sclerosis is a different type of multiple sclerosis, and it is initially diagnosed in 15 percent of individuals with a new diagnosis. It is characterized by neurological progression from the onset of presentation, without relapses and remissions early in the course of disease (National Multiple Sclerosis Society, n.d.-b, 2020; Thompson et al., 2018).

Epidemiology and Impact

Information on disparities in the epidemiology of multiple sclerosis can be found in Box 3-9.

Complications, Other Morbidity, and Long-Term Consequences

There is significant clinical heterogeneity in multiple sclerosis, with a varied accumulation of disability. The disease is a major cause of disability in young adults, particularly if it enters a progressive phase with persistent, non-remitting neurologic manifestations (Dimitrov and Turner, 2014). There are also substantial financial and psychosocial costs to the individual and society (Rodriguez-Rincon et al., 2019; Schriefer et al., 2021).

Complications that commonly accompany multiple sclerosis include urinary tract infections from bladder dysfunction and pressure ulcers resulting from immobility. Research has yet to determine whether depression is a primary manifestation, a complication of multiple sclerosis, or both. The lifetime risk of depression among those with multiple sclerosis is estimated to reach as high as 50 percent (Sadovnick et al., 1996), and the prevalence of depression is estimated to be 26 percent in the 18- to 45-year-old subgroup of those with multiple sclerosis (Patten et al., 2003). The occurrence of moderate to severe depressive symptoms in individuals with multiple sclerosis is approximately double that of age-matched individuals in the general population (Chan et al., 2021). Anxiety and sleep disorders—with or without memory problems—also appear to be more common in individuals with multiple sclerosis than in the general population (Bamer et al., 2008; Boeschoten et al., 2017; Hughes et al., 2018; Sumowski et al., 2021).

Other disorders that studies have found to have a higher prevalence in individuals with multiple sclerosis relative to populations without multiple sclerosis include hypertension, hypercholesterolemia, and chronic lung disease, though research has not identified the mechanisms for these associations (Magyari and Sorensen, 2020; Narula, 2016). Research has also shown that autoimmune disorders including type 1 diabetes, psoriasis, and IBD have a higher prevalence in persons with multiple sclerosis than in persons without the disease (Magyari and Sorensen, 2020).

Economic Impact

A 2013 review of studies examining the health care costs of multiple sclerosis noted that the estimated annual direct costs per patient of $21,238 in 2011 dollars were second only to congestive heart failure (Adelman et al., 2013). The studies cited in the review were conducted between 1999 and 2008 and so would not have included costs of newer, more expensive drug therapies.

Risk Factors and Etiology

The cause of multiple sclerosis is not known, though research has identified a number of genetic and environmental factors that increase the risk of developing multiple sclerosis. Much of the evidence suggests that multiple sclerosis results when one or more environmental factors interact with a genetic predisposition to the disease. The risk of developing multiple sclerosis is up to 20 percent higher for individuals with a parent or sibling with multiple sclerosis compared with those with no family history of the disease (Compston and Coles, 2002, 2008), which suggests the influence of both genetic and environmental factors. The main marker of genetic susceptibility to the disease is located in the HLA coding region of the human genome, although research has identified more than 200 other loci affecting risk (Canto and Oksenberg, 2018). In addition to the genetic risk, epidemiological studies have identified numerous environmental risk factors for the development and/or progression of multiple sclerosis, including exposure to EBV (Biström et al., 2021; Langer-Gould et al., 2017), early-life obesity, vitamin D deficiency, cigarette smoking, and exposure to air pollution (Aa Høglund et al., 2021; Ascherio and Munger, 2016; Huppke et al., 2019; Munger et al., 2016; Noorimotlagh et al., 2021). A recent study of more than 10 million active-duty U.S. personnel between 1993 and 2003 found that risk of developing multiple sclerosis increased 32-fold after infection with EBV (Bjornevik et al., 2022). Exposure to early-life obesity, smoking, or EBV appear to interact with an HLA risk allele to result in an even higher risk of multiple sclerosis, although the biological explanations for these gene-environment interactions are far from clear (Hedström et al., 2021; Olsson et al., 2017). Increasingly, research is showing that the gut microbiome is a potential factor in the development of multiple sclerosis (Burton, 2018).

Diagnostic Tools

There is no single feature or diagnostic test for multiple sclerosis. Rather, clinicians make a diagnosis of multiple sclerosis based on a combination of historical and physical examination, and imaging findings. Diagnostic criteria proposed in 1965 and 1983 called for a multiple sclerosis diagnosis based on two separate attacks of neurologic symptoms, including motor, sensory, or visual disturbances, that are disseminated in terms of the location of CNS lesions and occur at least 1 month apart, excluding other diseases with similar features (Poser et al., 1983; Schumacher et al., 1965). The 1983 guidelines aimed to establish more objective and standardized diagnostic criteria, as well as supporting laboratory features including presence of increased IgG levels in the cerebrospinal fluid but normal levels in serum (Poser et al., 1983).

Newer diagnostic criteria proposed in 2001, 2005, and 2010 incorporate brain MRI criteria for establishing dissemination of CNS lesions in space and time (Polman et al., 2011). Brain MRI is the most sensitive test to estimate CNS lesion load and disease activity, progression, and prognosis. More recent criteria proposed in 2010 and 2017 enable a diagnosis from a single baseline MRI, which has the potential to result in earlier and more accurate diagnosis and lead to prompt treatment (Milo and Miller, 2014; van der Vuurst de Vries et al., 2018). Despite these advances, it remains challenging to diagnose multiple sclerosis because early symptoms can be vague and transient. In addition, there is no specific biomarker or laboratory test for multiple sclerosis (Solomon et al., 2019), and misdiagnosis can occur when the symptoms mimic those of other disease and healthy states (Calabrese et al., 2021).

There is increasing evidence that there are early signs of symptoms of multiple sclerosis that appear before the first overt symptoms appear (Giovannoni, 2017). MRI studies have detected asymptomatic lesions, especially during the early course of disease. In fact, MRI scans of asymptomatic first-degree relatives of people with multiple sclerosis find brain lesions in approximately 10 percent of those individuals. These lesions could indicate demyelination is occurring. Because these lesions fulfill the requirement to be disseminated in the CNS, this finding suggests there may be an asymptomatic preclinical state (De Stefano et al., 2006; Xia et al., 2017). In addition, clinically isolated syndrome refers to a single episode of neurologic symptoms lasting at least 24 hours and meeting other criteria that rules out other causes of the symptoms. If neuroimaging studies show abnormalities consistent with demyelination in the region that correlates with the neurologic symptoms, there is a 60–80 percent risk of developing multiple sclerosis within the next few years; when neuroimaging abnormalities are not present, there is a much lower (~20 percent) chance of developing multiple sclerosis over a similar time frame (National Multiple Sclerosis Society, n.d.-a). Initiation of disease-modifying therapy is often recommended, particularly for the high-risk category of clinically isolated syndrome (Jokubaitis et al., 2015a; National Multiple Sclerosis Society, n.d.-d; Tsivgoulis et al., 2015).

Treatment and Prospects for Cures

FDA approved the first disease-modifying therapy for multiple sclerosis in the United States in 1993 (Loma and Heyman, 2011). Since then, FDA has approved a host of other agents that can be administered by pill, injection, or infusion (National Multiple Sclerosis Society, n.d.-c). These disease-modifying therapies target various aspects of the immune system to reduce the CNS inflammation that occurs in multiple sclerosis.

Disease-modifying therapies are generally most effective in those who have relapsing-remitting disease, have more active disease (as detected by MRI), who are younger, and who are less disabled (National Multiple Sclerosis Society, n.d.-b, 2020; Signori et al., 2015), with treatment delays associated with more clinical symptoms and more abnormalities in MRI scans (Comi, 2013; Deangelis and Miller, 2014; Jokubaitis et al., 2015b; Kavaliunas et al., 2017; Kinkel et al., 2006). To date, FDA has approved only one medication, ocrelizumab, for primary progressive multiple sclerosis (FDA, 2017a).

The National Multiple Sclerosis Society⁷ website provides an overview of disease-modifying therapies for multiple sclerosis. A subgroup of disease-modifying therapies is characterized as “high-efficacy” or “highly effective” as they are more potent, but they usually also have a higher risk of serious side effects (Merkel et al., 2017). A thorough discussion of pros and cons is recommended for shared decision-making with patients (Col et al., 2019). Several international studies suggest that the advent of disease-modifying therapies has altered the natural history of relapsing-remitting multiple sclerosis (Beiki et al., 2019; Simonsen et al., 2021). Autologous hematopoietic stem-cell transplant (also known as bone marrow transplant) has been recommended as having sufficient evidence to be carefully considered for the minority of patients with multiple sclerosis whose disease activity is substantial and continues despite treatment with even a high-efficacy disease-modifying therapy, or for patients for whom there is a contraindication to a disease-modifying therapy. Owing to the serious risks that accompany this treatment, the National Multiple Sclerosis Society’s National Medical Advisory Committee recommends that candidates under the age of 50 and with disease of less than 10 years’ duration may have a better risk/benefit ratio for this aggressive treatment (Miller et al., 2021). As noted previously, fatigue is a symptom that significantly adversely affects many with multiple sclerosis. There is evidence that some behavioral and exercise interventions directed at reducing fatigue and its impact can be beneficial (Moss-Morris et al., 2021). With an estimated lifetime risk of depression in multiple sclerosis reaching as high as 50 percent, periodic screening and assessment, and implementation of treatment, is recommended (Patten, 2020; Skokou et al., 2012). Spasticity, balance and gait, and impairment in functional status are ideally addressed with rehabilitation and other modalities (Donzé and Massot, 2021).

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⁷ Available at https://www.nationalmssociety.org/Treating-MS/Medications#section-2 (accessed December 29, 2021).

Animal Models

Investigators have developed several animal models to study aspects of the pathogenic mechanisms driving autoimmunity directed against the CNS (Procaccini et al., 2015). The most commonly studied is the experimental autoimmune encephalomyelitis (EAE) mouse model, in which immunizing the mice with specific proteins or peptides targeted by the immune system in multiple sclerosis induces an autoimmune demyelinating disease (Constantinescu et al., 2011). The specific features of disease that develop depend on the antigen used and the genetic strain of mouse, with some developing chronic CNS inflammation and others developing a relapsing-remitting course. This variability enables researchers to study the different disease courses seen in humans and has provided information regarding the autoimmune response, but the need to induce disease with immunization yields a more artificial model than in spontaneous models of the disease. Identification of specific peptides targeted by autoreactive T cells in EAE mouse model studies has led researchers to develop mice that they genetically engineer to express the pathogenic T-cell receptors, which results in an overabundance of pathogenic T cells that target the self-antigen and the spontaneous development of EAE (Frausto et al., 2007; Goverman, 2009).

In addition to EAE, researchers have developed procedures for inducing rodents to develop a demyelinating disease following infection with certain viruses, such as Theiler’s murine encephalomyelitis virus or treatment with certain toxins (Gerhauser et al., 2019). Together, these models have enabled detailed studies of immune and non-immune features of demyelinating disease, including visualizing the interactions between cells within the brain and spinal cord, which is not as easily performed or studied in humans.

Research Progress and Gaps

Regarding pathophysiology and identifying targets for treatment of multiple sclerosis, ongoing research includes investigating the role of the gut microbiome as well as the pathways by which inflammatory cells breach the barriers into the CNS. Genetic studies are investigating complex gene–environment interactions (Horng et al., 2017; Takewaki and Yamamura, 2021). While there has been substantial progress in using disease-modifying therapies to treat relapsing-remitting multiple sclerosis, there is currently limited evidence for therapies that slow progression in the progressive type of the disease. Given the greater prevalence of multiple sclerosis among women of child-bearing years, and the welcome advent of disease-modifying therapies, research to generate evidence on

the optimal management of multiple sclerosis before, during, and after pregnancy is needed. While there have been animal studies that have yielded targets for CNS remyelination, there are barriers to translating this knowledge to develop remyelination therapies, such as how to best design and best evaluate clinical trials (Lubetzki et al., 2020). The association of low vitamin D with disease onset and relapse frequency warrants further investigation of whether intervention to raise vitamin D levels can affect disease course (Mansoor et al., 2021). The roles of stem-cell transplantation and other cell therapies are not fully developed.

There is a substantial need to develop early-detection techniques to enable treatment to begin as early as possible. Early biomarkers, such as autoantibody screens and additional MRI indicators, are needed to detect disease sooner, before irreversible damage occurs. Early biomarkers would be particularly valuable for screening higher-risk, asymptomatic family members of people with multiple sclerosis who are more likely to have early subclinical manifestations of the disease. Developing early markers would benefit from cohort studies that follow high-risk individuals longitudinally. Prospective, longitudinal studies would also enable the study of multiple sclerosis from a life-course perspective. While several registries have been developed around the world in recent decades, one review found “a significant number of largely uncoordinated parallel studies,” and many of them use convenience samples (Bebo et al., 2018). From a public health perspective, there is a need to develop systems by which researchers can obtain reliable epidemiological data regarding the prevalence, incidence, and time trends of multiple sclerosis.

In addition, there is a need for health-services research to investigate and design interventions to overcome delays in the diagnosis of multiple sclerosis, including delays that differentially affect non-White persons and women, as well as those with decreased access to health care. Risk-stratification and prediction algorithms are needed to predict who is likely to have a more aggressive disease course as a means of guiding decision-making around the selection and sequence of use of disease-modifying therapies and other emerging therapies.

Treatments to manage the “invisible” symptoms of multiple sclerosis that have profound impacts on health-related quality of life, including fatigue, depression, and anxiety, lack a body of evidence, despite many promising leads (Lakin et al., 2021). The potential value of Chronic Care Model-based approaches in providing comprehensive multiple sclerosis care and implementing strategies to optimize care and patient outcomes is understudied, yet as the United States moves toward value-based payment models, such research evidence is needed to guide implementation of coordinated chronic care that will maximize patient outcomes (Cotton et al., 2016).

TYPE 1 DIABETES

Type 1 diabetes is characterized by autoimmune damage, impairment, and eventual destruction of the insulin-producing pancreatic beta cells, which leads to a dependence on administered insulin. If not treated with insulin, type 1 diabetes leads to hyperglycemia, which, if unchecked, results in deadly diabetic ketoacidosis and coma in an acute state, and microvascular and macrovascular end-organ complications in a chronic state. Type 1 diabetes is generally preceded by the appearance of islet autoantibodies in the blood, defined as islet autoimmunity; however, not all those who develop islet autoimmunity progress to type 1 diabetes (Kwon et al., 2022; Regnell and Lernmark, 2017).

Epidemiology and Impact

Information on disparities in the epidemiology of type 1 diabetes can be found in Box 3-10.

Complications, Other Morbidity, and Long-Term Consequences

Diabetic ketoacidosis and severe hypoglycemia are acute and potentially life-threatening complications of type 1 diabetes. While type 1 diabetes is more common in non-Hispanic White people, the frequency of diabetic ketoacidosis is higher among ethnic minority, individuals with lower socioeconomic status, and those who lack private health insurance (Rewers, 2018). The percentage of hospitalizations for severe hypoglycemia is higher in males compared with females and lower in White persons than in any other racial or ethnic group (Rewers, 2018). The chronic complications of type 1 diabetes include microvascular and macrovascular conditions. Individuals with type 1 diabetes are at increased risk for retinopathy leading to sight-loss/blindness (Klein and Klein, 2018), nephropathy leading to ESRD (Pavkov et al., 2018), and neuropathy and peripheral vascular disease leading to amputation (Boyko et al., 2018).

Individuals with type 1 diabetes are at increased risk of conditions such as heart disease and stroke (Barrett-Connor et al., 2018; Mayo Clinic, 2020b), as well as co-occurring autoimmune illnesses, particularly celiac disease (Cohn et al., 2014). A recent large study in Finland found that one out of five persons with type 1 diabetes develops one or more additional autoimmune diseases, with Graves’ disease, Hashimoto’s thyroiditis, and celiac disease being among the most common (Barker, 2006; Makimattila et al., 2020). The prevalence of depression is significantly higher in individuals with type 1 diabetes compared with those without diabetes (Farooqi et al., 2021). Eating disorders are twice as common in adolescent females with type 1 diabetes compared with those without diabetes, though few studies on this topic are available (Jones et al., 2000).

Individuals with type 1 diabetes are more likely to develop infections, such as bone and joint infections (Schwartz, 2018), acute cholecystitis, gastrointestinal infections, mycoses, pneumonia, sepsis, surgical site infections, endocarditis, meningitis, urinary tract infections, cellulitis, lower extremity infections and foot ulcers, and tuberculosis compared with individuals without type 1 diabetes (Carey et al., 2018; NIDDK, 2018a). Data consistently show that diabetes increases risk of severe COVID-19 (Hartmann-Boyce et al., 2021), although most studies did not distinguish between type 1 and type 2 diabetes. One population study in the United Kingdom found that the risk of in-hospital COVID-19-related death was markedly higher in people with type 1 diabetes compared with those with type 2 diabetes (Barron et al., 2020; Holman et al., 2020).

Type 1 diabetes increases the risk of mortality, stroke and cerebrovascular complications, myocardial infarction, and pre-eclampsia in pregnant individuals (NIDDK, 2018a). Women with type 1 diabetes have a higher risk of having infants with macrosomia and associated birth trauma, respiratory distress, and congenital malformations compared

with women without type 1 diabetes. The risks of poor outcomes in the mother and newborn are mitigated with better glycemic control during pregnancy although this requires intensive care and monitoring (Alexopoulos et al., 2019; Lemaitre et al., 2021; NIDDK, 2018a).

Economic Impact

Individuals with type 1 diabetes incur, on average, $1,981 more per year in medical costs than those without type 1 diabetes. The expected lifetime medical costs for all people with type 1 diabetes exceeds $130 billion (Tao et al., 2010).

Risk Factors and Etiology

In type 1 diabetes, the body’s immune system mistakenly destroys the insulin-producing islet cells in the pancreas, leading to hypoglycemia and clinical diabetes. Type 1 diabetes is characterized by the presence of autoantibodies years prior to the diagnosis of the disease, making them strong serologic markers of preclinical disease. The autoantibodies that precede type 1 diabetes include antibodies to insulin, glutamic acid decarboxylase, islet antigen 2, and zinc transporter family member 8 antigens (Pietropaolo et al., 2012). While development of islet autoimmunity is highly predictive of future type 1 diabetes, not all those who develop islet autoimmunity progress to disease (Regnell and Lernmark, 2017). It is unknown what factors trigger this autoimmune attack and whether similar or different factors perpetuate the autoimmunity that eventually results in disease.

Genetics play a key role in type 1 diabetes etiology, with the strongest risk alleles mapped to the HLA region of the genome. Large-scale studies show that type 1 diabetes is a polygenic disease with more than 40 risk loci (Barrett et al., 2009). However, the incidence of type 1 diabetes has been increasing at an exponential rate (Onkamo et al., 1999), a change that is too rapid to be explained by genetic factors alone, which suggests a role for non-genetic factors in disease etiology (Norris et al., 2020).

While researchers have investigated several candidate environmental factors, they have yet to fully elucidate what role they play in the development of type 1 diabetes. Of these candidate environmental factors, a large number are related to in utero or neonatal exposures, including higher maternal age at delivery, higher maternal pre- or early-gestational obesity, maternal virus infections, and Cesarean section (Norris et al., 2020; Yue et al., 2018). However, given the relatively low incidence of the disease, it is difficult and costly to obtain data to investigate these factors. Researchers are also examining exposures during infancy, including increased infant

growth, shorter duration of breastfeeding, and timing of the introduction of solid foods, and omega-3 fatty acid intake and status (Norris et al., 2020). Research has provided some evidence that childhood exposures, such as higher cow’s milk intake, higher gluten intake, higher sugar intake, lower vitamin D status, and enterovirus infection, are candidate risk factors for type 1 diabetes (Norris et al., 2020).

Diagnostic Tools

It is possible to diagnose a clinical state of type 1 diabetes using an elevated 2-hour glucose measure during an oral glucose tolerance test, a high hemoglobin A1C blood test, two high random blood-sugar tests coupled with any of the signs and symptoms of diabetes, or two high fasting blood-sugar tests.

There are three distinct stages of type 1 diabetes (Insel et al., 2015). Stage 1 is defined by the presence of two or more diabetes-related autoantibodies in the blood with normal blood glucose levels (Insel et al., 2015). Stage 2 commences when blood glucose levels begin to rise, signaling functional impairment of the islet cells. Stage 3 occurs when symptoms of glucose dysregulation, such as the production of abnormally large volumes of dilute urine or diabetic ketoacidosis, appear. While a clinical diagnosis is made only at Stage 3, the likelihood of progressing from Stage 1 to Stage 3 is very high, with a 5- and 10-year risk of 44 percent and 70 percent, respectively (Insel et al., 2015; Ziegler et al., 2013; Zuily et al., 2015).

Treatment and Prospects for Cures

Treatment for type 1 diabetes includes insulin therapy; dietary carbohydrate, fat, and protein counting; and frequent blood-sugar monitoring. The goal of treatment is to keep blood-sugar level as close to normal as possible and delay or prevent complications. Insulin therapy involves either multiple daily insulin injections or use of an insulin pump, a device worn outside of the body that dispenses insulin as needed. In 2019, FDA approved the “artificial pancreas,” an implanted closed-loop insulin delivery device, for individuals with type 1 diabetes (FDA, 2018a, 2019). A Phase III clinical trial of pancreatic islet transplantation in persons with type 1 diabetes who have impaired awareness of hypoglycemia and are at elevated risk of severe hypoglycemic events showed improvement in blood glucose awareness and control (Hering et al., 2016) as well as quality of life (Foster et al., 2018). Studies have demonstrated that people who maintain tight blood glucose control in the early stages of disease are less likely to undergo retinopathy eye surgeries (DCCT/EDIC Research Group

et al., 2015) and are likely to live longer compared with those who do not (Writing Group for the DCCT/EDIC Research Group et al., 2015).

In studies of infants at risk for type 1 diabetes, one diet-manipulation study that replaced cow’s milk-based infant formula with hydrolyzed infant formula had no effect on the incidence of islet autoantibodies (Knip et al., 2014) or diabetes (Writing Group for the TRIGR Study Group et al., 2018), while another study that removed bovine insulin from infant formula showed a decrease in incidence of islet autoimmunity at 3 years of age (Vaarala et al., 2012). A third study found that delaying gluten exposure until age 12 months did not substantially reduce the risk of islet autoimmunity (Hummel et al., 2011). Interventions targeting the immune system have not slowed, halted, or reversed the destruction of insulin-producing beta cells (Skyler et al., 2018). Only one of nine secondary prevention trials—a trial of the anti-CD3 antibody teplizumab (Herold et al., 2019)—showed any delay in progression of individuals with Stage 1 or Stage 2 disease to full-blown type 1 diabetes (Diabetes Prevention Trial—Type 1 Diabetes Study Group, 2002; Elding Larsson et al., 2018; Gale et al., 2004; Krischer et al., 2017; Lampeter et al., 1998; Näntö-Salonen et al., 2008; Vandemeulebroucke et al., 2009; Vehik et al., 2011).

Animal Models

Three spontaneous autoimmune animal models, including the non-obese diabetic mouse, the biobreeding Komeda rat, and the LEW.1AR1iddm rat, are the primary animal models for studying type 1 diabetes (Al-Awar et al., 2016; King, 2012; Kottaisamy et al., 2021). These models allow the researcher to examine beta cell destruction during an autoimmune process, probe the genetics and mechanisms underlying type 1 diabetes, manipulate the autoimmune process, and study treatments that prevent beta cell death. Genetically induced models include the AKITA mouse and the KINGS Ins2^+/G32S mouse, which demonstrate beta cell destruction resulting from endoplasmic reticulum stress (King, 2012). Researchers can use them as transplantation models and to develop new insulin formulations and treatments to prevent endoplasmic reticulum stress. Virally induced animal models enable researchers to investigate beta cell destruction induced by viral infection of the beta cells, while chemically induced models are useful as transplantation models and for investigating new formulations of insulin and treatments that may prevent beta cell death (King, 2012).

Research Progress and Gaps

Medical science has made great strides in treating type 1 diabetes and preventing its complications. The nation has built a critical research infrastructure to investigate the prevention of type 1 diabetes, including clinical trial networks such as TrialNet and the Immune Tolerance Network. While there have been a number of clinical trials, only one has been successful to date in delaying progression to type 1 diabetes. Other research infrastructure includes large natural history studies, such as TEDDY, DAISY, Germany’s BABYDIAB study,⁸ and the Type 1 Diabetes Prediction and Prevention Study,⁹ many of which NIH funds. These large birth cohort studies have enabled researchers to investigate the life course of type 1 diabetes, providing important clues as to the appropriate timing and approaches for prevention. The Type 1 Diabetes Genetics Consortium has thoroughly explored the genetics of type 1 diabetes. The SEARCH for Diabetes in Youth study and other population-based registries, such as the Colorado and Pittsburgh Insulin-Dependent Diabetes Mellitus registries, have enabled researchers to determine the incidence and prevalence of type 1 diabetes in the United States.

Technology advances are greatly simplifying the effort required by patients of all ages to monitor and control their blood glucose levels. In addition, pancreatic islet transplantation has shown benefit in patients with hard-to-control blood glucose levels who are at elevated risk of hypoglycemic events (NIDDK, 2018b).

Despite this infrastructure and progress, there remain gaps in knowledge about type 1 diabetes. The planned termination of TEDDY, in 2025 (Clinicaltrials.gov, 2006) illustrates a concern about ending valuable studies prematurely. This observation study, which has focused on the development of autoimmune diseases in newborns at risk of developing type 1 diabetes (NIDDK, 2021b), has gathered valuable data and samples. However, with a follow-up of only 15 years, many participants who are likely to develop disease will be disenrolled before clinical diagnosis, and disease-associated autoantibodies will not be tracked long enough to discern natural evolution or clinical outcomes.

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⁸ The German BABYDIAB study was a prospective German multicenter study that monitored 1,353 offspring of parents with type 1 diabetes (Ziegler et al., 1999). Children were monitored at birth, 9 months, and 2, 5, and 8 years of age for the temporal development of autoantibodies.

⁹ The DIPP Study is a Finnish prospective observational cohort study of infants born with a DR-DQ genotype associated with increased risk for type 1 diabetes (NLM, 2020). The families are invited to have examinations of the infant every 3 months for 2 years, and then every 12 months until age 15 or until diagnosis of type 1 diabetes.

Research to identify the exact environmental triggers (including whether or not environmental factors differentially influence risk in different racial and ethnic groups, and gene-environment interactions), and understand the role of the in utero environment, inflammation, and pancreatic beta cell stress in the etiology of type 1 diabetes is necessary. Additional investigation as to why some individuals develop autoimmunity but do not advance to type 1 diabetes may provide valuable information regarding how to stop the autoimmune process from progressing and thus prevent clinical disease. While it is estimated that half of all type 1 diabetes presents after the age of 18, there is a paucity of data on adult-onset type 1 diabetes.

AUTOIMMUNE THYROID DISEASES

Autoimmune thyroid diseases are believed to be among the most common autoimmune diseases, and among them are Hashimoto’s thyroiditis and Graves’ disease, which are the leading causes of hypothyroidism and hyperthyroidism, respectively (Franco et al., 2013). In both of these diseases, autoantibodies attack the thyroid gland. In Hashimoto’s thyroiditis, this autoantibody attack may have no effect on the thyroid initially, or it may cause the thyroid to be underactive, or rarely, overactive. In most individuals, however, the thyroid eventually becomes underactive, resulting in an enlargement of the thyroid and sometimes fatigue and decreased tolerance to cold (Hershman, 2020a). In Graves’ disease, the thyroid is stimulated to produce and secrete excess thyroid hormones, which typically lead to an enlarged thyroid and increased bodily functions such as heart rate and blood pressure, which can yield excessive sweating, anxiety, weight loss, and difficulty sleeping (Hershman, 2020b). Graves’ disease can also affect the eyes, causing symptoms such as tearing, redness, pain, vision problems, and bulging eyes (Watson, 2021).

Epidemiology and Impact

Information on disparities in the epidemiology of autoimmune thyroid disease can be found in Box 3-11.

Complications, Other Morbidity, and Long-Term Consequences

A number of risks are associated with hypo- or hyper-thyroidism that occurs for prolonged periods, even if the disease is subclinical or asymptomatic, such as from undiagnosed thyroid disease or under- or overtreatment. Risks include elevated mortality, dementia, cardiovascular diseases, and osteoporosis (Abrahamsen et al., 2014; Lillevang-Johansen et al., 2017, 2018, 2019). Women may have an increased risk of infertility, miscarriage, and preterm delivery, and there may be adverse effects on neurodevelopment in their children (Galofre and Davies, 2009). Between 25 and 50 percent of individuals with Graves’ disease develop Graves’ orbitopathy, a condition that can cause eye inflammation, swelling, irritation, and pain as well as eyelid retraction and bulging eyes; it can be disfiguring and can endanger sight (MedlinePlus, 2020).

Hashimoto’s thyroiditis is associated with an increased risk of thyroid cancer (Penta et al., 2018; Resende de Paiva et al., 2017) as is Graves’ disease, particularly in persons with thyroid nodules (Chen et al., 2013; Staniforth et al., 2016). While findings are mixed regarding an increased risk of breast cancer in those with Graves’ disease, it is recommended that these patients be monitored (Chen et al., 2013; Yang et al., 2020).

Persons with an autoimmune thyroid disease are at a greater risk of developing other autoimmune diseases than persons without an autoimmune thyroid disease. One cross-sectional study of more than 3,000 White UK patients with Graves’ disease or Hashimoto’s thyroiditis observed a relative risk greater than 10.0 of developing pernicious anemia, SLE,

Addison’s disease (particularly in men with Hashimoto’s thyroiditis), myasthenia gravis (in men with Graves’ disease and women with Hashimoto’s thyroiditis), celiac disease, vitiligo, and multiple sclerosis (in men with Hashimoto’s thyroiditis) (Boelaert et al., 2010). Sjögren’s disease is also highly associated with autoimmune thyroid diseases (Baldini et al., 2018; Rojas-Villarraga et al., 2012).

Individuals with Hashimoto’s thyroiditis are at an increased risk of developing depression and anxiety disorders (Siegmann et al., 2018). Depression is common in Graves’ disease (Fukao et al., 2020), and experiencing disfigurement increases emotional distress (Farid et al., 2005).

Economic Impact

A study published in 2021 estimated that annual per patient medical costs related to hypothyroidism ranged from $460 to $2,555 (Hepp et al., 2021). However, this study was not restricted to autoimmune hypothyroidism and did not assess the economic costs of Graves’ disease or Hashimoto’s thyroiditis.

Risk Factors and Etiology

A temporal increase in disease incidence over a relatively short time, such as that observed in the Rochester, Minnesota, population for autoimmune thyroid diseases, supports the hypothesis that environmental factors play a key role in the development of disease. Dietary factors are leading contenders among suspected risk factors. There is some evidence that in iodine-sufficient areas, excess iodine intake may be associated with development of hypothyroidism in susceptible individuals (Konno et al., 1994; Laurberg et al., 1998; Sundick et al., 1992). While iodine is essential for normal thyroid function, both deficient and excessive intake have been associated with autoimmune thyroid disease. Selenium deficiency is another dietary factor that has been linked to autoimmune thyroid disease, and studies of supplementation among persons with subclinical hypothyroidism have suggested reduction in markers of thyroid autoimmunity (Duntas et al., 2003; Gärtner et al., 2002).

Smoking is associated with autoimmune thyroid disease; a metaanalysis reported an odds ratio of 3.3 for Graves’ disease in current smokers compared with non-smokers. (Vestergaard, 2002). Data suggest that smoking is particularly relevant to the development of Graves’ ophthalmopathy (Hägg and Asplund, 1987; Prummel and Wiersinga, 1993). Studies have shown that a number of toxins, including polychlorinated biphenyls, phthalates, bisphenol A, and brominated flame retardants, may have thyroid-disrupting effects, but long-term epidemiologic data

assessing exposures over varying developmental stages, including in utero, are needed to determine whether these substances play any role in the development of autoimmune thyroid disease (Boas et al., 2012).

Investigators have also postulated that infectious agents play a role in the development of autoimmune thyroid diseases, with evidence accumulating in particular for hepatitis C (Deutsch et al., 1997) and its treatment with interferon-α (IFNα). Clinical or subclinical thyroid disease develops in approximately 40 percent of patients with hepatitis C treated with IFNα. IFNα-induced thyroiditis is thought to result from both immune effects and direct toxicity on the thyroid, with both autoimmune and non-autoimmune thyroiditis observed in association with this therapy (Menconi et al., 2011).

Genetic susceptibility also plays a key role in both Hashimoto’s thyroiditis and Graves’ disease, with family studies demonstrating high sibling risk ratios and twin concordance (Tomer, 2014). Research has implicated both thyroid-specific genes such as those coding for thyroglobulin and thyroid-stimulating hormone receptor, and immune-regulatory genes. Hashimoto’s thyroiditis and Graves’ disease share most of the susceptibility genes, and several are also shared with other autoimmune diseases (Tomer, 2014). Most of the susceptibility genes identified from genome-wide association studies have low odds ratios (Chu et al., 2011; Cooper et al., 2012; Hodge and Greenberg, 2016), pointing to the importance of genomic interactions with environmental factors. Recent research supports the role of epigenetic modulation in the development of Hashimoto’s thyroiditis and Graves’ disease (Tomer, 2014).

Diagnostic Tools

While symptoms of autoimmune thyroid disease are generally nonspecific, such as weight change, changes in appetite, fatigue, and dry skin, diagnosis relies on objective laboratory testing for thyroid hormone, thyroid–stimulating hormone, and autoantibodies. The major autoantibodies include anti-thyroid peroxidase, anti-thyroglobulin, and anti-thyroid-stimulating hormone receptor antibodies (Frohlich and Wahl, 2017). These autoantibodies are highly prevalent among patients with autoimmune thyroid disease, but are not specific in that they can also be observed in persons without thyroid disease.

Treatments and Prospects for Cures

Although clinical guidelines for autoimmune thyroid diseases have been updated, the standard therapies for autoimmune thyroid diseases have remained stagnant for several decades, are associated with serious

complications, and do not target underlying autoimmune processes (Yoo and Chung, 2016). Anti-thyroid medications, thyroid ablation with radioactive iodine, or surgery are treatments for Graves’ hyperthyroidism. Potential toxicities of anti-thyroid medications include agranulocytosis, liver toxicity, and birth defects (Andersen et al., 2013; Cooper, 2005), and the use of these medications is largely limited to serving as a bridge therapy prior to radioiodine or thyroidectomy. Radioiodine can trigger or worsen Graves’ ophthalmopathy, may increase risk of breast and other solid cancers (Kitahara et al., 2019), and is associated with pregnancy complications for up to 3 to 5 years after treatment. Risks associated with thyroidectomy include vocal cord paralysis and hypocalcemia. Thyroid hormone replacement is used following radioiodine therapy or thyroidectomy for Graves’ disease as well as for treatment of Hashimoto’s thyroiditis. However, inconsistent absorption and bioavailability create challenges in achieving appropriate levels, with over half of patients undergoing thyroid hormone replacement failing to have normal thyroid hormone levels (Somwaru et al., 2009). In addition, bioequivalence may vary between thyroxine products, such as between brands and generics, and since imprecise treatment can have adverse effects, it is important to switch brands with caution and to use appropriate monitoring (Benvenga and Carlé, 2019).

There is a great need for targeted therapies that address immunological aspects of autoimmune thyroid diseases and that have fewer side effects, and there have been promising advances in that regard. Teprotumumab, a monoclonal antibody that inhibits insulin-like growth factor-1 receptor, was originally investigated as a cancer treatment but received FDA approval in 2020 for treatment of Graves’ opthalmopathy (Kahaly et al., 2021; Slentz et al., 2020).

A novel anti-CD40 monoclonal antibody, iscalimab, is currently in clinical trials for treatment of Graves’ disease (Kahaly et al., 2020). This therapy builds on several years of basic and translational research elucidating the role of CD40 in Graves’ disease, as well as other autoimmune diseases (Jacobson et al., 2005; Tomer et al., 2002). Ongoing research is investigating a personalized medicine approach for this treatment that aims to determine whether response can be predicted based on genotype.

Another promising compound for treatment of autoimmune thyroid disease is cepharanthine, which is currently in preclinical studies (Li et al., 2016, 2020). This small molecule blocks binding of thyroglobulin peptide and presentation to T cells, providing a targeted immunosuppression. It also represents another therapy that may offer a personalized treatment approach, predicted to be relevant for a subset of approximately one-third of patients with autoimmune thyroid disease.

Animal Models

Experimental autoimmune thyroiditis can be induced by immunization of genetically susceptible animals with human thyroglobulin in an adjuvant and has served as a model for Hashimoto’s thyroiditis (Kong, 2007). Graves’ hyperthyroidism can be induced by injecting cells expressing the thyroid-stimulating hormone receptor or by vaccinating with thyroid-stimulating hormone receptor-encoding DNA in plasmid or adenoviral vectors (McLachlan et al., 2005). More recently, researchers have used the NOD.H-2h4 mice, one of relatively few animal models to spontaneously develop organ-specific autoimmune diseases without immunization with antigen and adjuvant, as a model of autoimmune thyroiditis (Braley-Mullen and Yu, 2015).

Research Progress and Gaps

FDA approval in 2020 of a monoclonal antibody for treatment of Graves’ opthalmopathy represented a major advance in this field, where the majority of treatments have remained unchanged over decades. Despite progress in understanding of molecular mechanisms driving autoimmune thyroid diseases, there remains a need to improve understanding of risk factors and disease mechanisms and to translate these findings into development or repurposing of targeted interventions for prevention or treatment. Improved characterization of biomarkers and their implications for diagnosis is also needed in order to personalize screening and treatment approaches. Given the challenges and complications related to both undiagnosed and treated autoimmune thyroid diseases during preconception and pregnancy, special consideration to reproductive issues should be integrated into research. Additionally, studies are needed to assess the economic costs and impact of Graves’ disease and Hashimoto’s thyroiditis.

SUMMARY AND RESEARCH IMPLICATONS

Sjögren’s disease, SLE, APS, rheumatoid arthritis, psoriasis, IBD, celiac disease, PBC, multiple sclerosis, type 1 diabetes, and autoimmune thyroid diseases are well-studied representatives of organ-specific and systemic autoimmune diseases. These illnesses share genetic, cell-biology, and etiologic mechanisms in diverse ways that with further study could lead to identifying specific autoimmune mechanisms involved in these diseases. Several treatment interventions are shared among some autoimmune diseases.

Most of these autoimmune diseases are female predominant, though they differ in median age of onset and racial and ethnic distributions. For

several, however, epidemiological studies are inadequate or nonexistent. Such studies should be encouraged to fully understand the incidence and prevalence of these diseases and any racial-, ethnic-, or gender-related disparities. Like all autoimmune diseases, the diseases reviewed above are chronic illnesses; some are lethal, others are disabling, and some are neither. With regard to pregnancy, autoimmune diseases and their treatments may affect both mother and fetus. Treatment options vary, with some diseases lacking FDA-approved treatment options altogether. None is easy to treat. None has a known cure.

Autoimmune diseases are heterogeneous. For some, diagnostic testing is well-established and diagnosis relatively straightforward. For others, diagnostic markers may be nonspecific, and final diagnosis may depend on variable combinations of symptoms, signs, laboratory markers, responses to treatment, genetics, and environmental exposure studies. For this latter group of autoimmune diseases, it is imperative to identify more specific diagnostic markers, both for the purposes of diagnosing these diseases as early as possible and to support efforts to develop effective therapeutics.

Co-occurrence of autoimmune diseases in individual patients is common. Complications arising from disease-inflicted damage and/or from treatment, occurring over prolonged periods of time, may hinder identification of broadly applicable interventions. In addition, a lack of standards for recording diagnosis codes and metrics for assessing outcomes make it difficult to determine the cost of care, disability, and mortality.

Animal models provide insight into pathophysiologic mechanisms of autoimmune disease to varying degrees, though no animal model perfectly recapitulates human autoimmune disease. Still, basic mechanisms of immune function and immune dysregulation can be more easily studied in appropriate animal models for specific diseases to provide a more directed, hypothesis-driven study of disease mechanisms in humans. Thus the value of animal models should be appreciated, and studies that develop new animal models or advance existing models are encouraged.

Despite the ambiguities, understanding the genetics, involvement of environmental exposures, and pathogenic mechanisms of autoimmune diseases suggest possibilities for initiatives to prevent disease. The second-hit hypothesis—that individuals may be genetically predisposed to develop clinical illness but do not do so unless and until exposures or events occur—is a theme common to all autoimmune diseases and one that merits further study, including whether such exposures or events differentially influence risk in specific ethnic and racial populations.

There are barriers to studying autoimmune diseases when there are rigid classification criteria for enrolling individuals with an autoimmune

disease diagnosis in a study.¹⁰ Among these are the prolonged time between autoimmunity onset and diagnosis, resulting from the absence of sensitive diagnostic biomarkers and clinician awareness of early disease manifestations; disease heterogeneity, including pre-diagnosis and in individuals who have overlapping autoimmune disease or who present atypically; and coexisting illnesses. Collaborative studies, using broad diagnostic criteria, provide opportunities to improve etiological, mechanistic, treatment, and outcome knowledge that could be applied to more patients and improve overall patient care.

Among the autoimmune diseases discussed in this chapter, no individual disease represents a full range of comprehensive studies or characterization. Sjögren’s disease, for example, represents a complex autoimmune disease that targets common self-antigens, disproportionately affects women, and may affect individuals across the life course. But limiting epidemiological studies in Sjögren’s disease to individuals with no co-occurring autoimmune disease has greatly hindered characterization of the full impact of Sjögren’s disease. Other diseases have been better characterized through epidemiological studies, including SLE, rheumatoid arthritis, IBD, and type 1 diabetes. Studies have best examined economic impact for the gastrointestinal diseases IBD and PBC. Type 1 diabetes represents a model autoimmune disease in that extensive study has identified autoantibodies to predict disease development and to enable intervention studies in individuals at highest risk for developing autoimmunity. Ultimately, this represents a key goal in autoimmune disease research—defining highly at-risk individuals and intervening to prevent progression to disease. Together these autoimmune diseases represent successes and gaps in our understanding that can be considered in the future funding and coordination of autoimmune disease research.

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¹⁰ Many systemic autoimmune diseases are predictable before they are diagnosable. For example, many patients who later develop SLE, type 1 diabetes, or PBC have blood test abnormalities—typically the presence of autoantibodies, which are sometimes associated with genetic markers—that antedate the onset of clinical illness by a decade. Similarly, a limited form of neurological illness known as clinically isolated syndrome may precede diagnosable multiple sclerosis. And nonspecific IBD may precede diagnosable Crohn’s disease or ulcerative colitis. The predictive power of pre-disease is not high, since many pre-disease patients do not progress to diagnosable disease. In most cases, it is unknown whether the differences between pre-disease and diagnosable disease reflect disease severity or chronology of disease pathogenesis. Clinicians, scientists, and administrators disagree whether pre-disease patients should be included in studies and conversations about specific diagnoses.

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