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Selected Immune Disorders and Disability (2022)

Chapter: 2 Cross-Cutting Issues

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Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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2

Cross-Cutting Issues

The focus of this chapter is on select issues that affect people across the spectrum of immune system disorders. These include comorbidities such as depression and anxiety, systemic manifestations such as pain and fatigue, and cognitive effects—all of which have a profound impact on the daily functioning of individuals who experience those effects. Other topics discussed in this chapter include issues that were raised in the committee’s Statement of Task, including: flares and remission, medication side effects, how treatments might indicate the severity of illness, and treatment settings and availability. Finally, the committee includes a short section on the impact of COVID-19 on immune system disorders. Organ-specific systemic effects are discussed in detail in each of the disease-focused chapters.

DEPRESSION AND ANXIETY

Depression is defined as depressed mood (sad, empty, hopeless, irritable) or the loss of interest or pleasure present nearly every day for a 2-week period in addition to physical changes (e.g., weight loss/gain, loss of energy, psychomotor slowing) and cognitive changes (e.g., difficulties concentrating, fatigue) that manifest in clinically significant distress or impairment in functioning across domains (APA, 2013). Anxiety is defined as excessive worry occurring more days than not for at least 6 months and that causes clinically significant distress or impairment in social, occupational, or other important areas of functioning (APA, 2013). The prevalence of depression and anxiety in the rheumatic diseases is about twice that of the general population (Geenan et al., 2012).

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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Depression and anxiety are common in all the rheumatic diseases. A systematic review of 59 studies estimated a prevalence of depression in those with systemic lupus erythematosus (SLE) to be 30 percent and a pooled prevalence of anxiety to be 40 percent (Zhang et al., 2017). Observational studies of rheumatoid arthritis (RA) patients have documented a prevalence of 22–38 percent for depression or anxiety, with a greater prevalence in women (Covic et al., 2012; Cunha et al., 2016). An observational study of systemic sclerosis patients estimated a prevalence of 36 percent for both depression and anxiety (Del Rosso et al., 2013). Prevalence estimates for depression in primary Sjögrens Syndrome (pSS) range from 8 percent to 76 percent (Cui et al., 2018). Psychiatric comorbidities are also commonly reported in childhood-onset rheumatic diseases, with a pooled prevalence of 13 percent for anxiety disorders and 20 percent for mood disorders (Jansson et al., 2022).

For individuals with a wide range of physical conditions, depression is the most common comorbidity affecting physical functioning and limiting employment (Greenberg et al., 2015; Kessler, 2003; NASEM, 2019). Depression and anxiety associated with SLE may be due both to the physical effect of the autoimmunity on the nervous system and to the suffering due to pain and disability. Carr and colleagues (2011) found that depression in SLE patients was correlated with higher self-reported disease activity. A study by Figueiredo-Braga and colleagues (2018) showed that serum levels of interleukin-10 (IL-10)1 appeared to be a good indicator of depression in SLE patients and that fatigue severity was strongly correlated with depression in SLE patients. In patients with SLE, anxiety disorders have been shown to be associated with cardiovascular disease including myocardial infarction as well as with suicidal ideation, physical disability, a reduced quality of life, and a high prevalence of premature mortality (Figueiredo-Braga et al., 2018; Jorge et al., 2017; Zhang et al., 2017).

RA is also associated with psychological manifestations, though not to the same extent as lupus. In patients with RA, depression has been shown to be associated with higher levels of pain and disability, poorer quality of life, increased suicidal ideation, and increased mortality (Beşirli et al., 2020), while depression and anxiety have been associated with an increase in disease activity along with a reduction in response to treatment and lower rates of remission (Boer et al., 2018; Imran et al., 2015; Michelsen et al., 2017). Furthermore, chronic inflammation can change the physiological response to stress and emotional reactions, thus increasing the risk of depression (Beşirli et al., 2020).

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1 Interleukin 10 (IL-10) is a cytokine with potent anti-inflammatory properties which plays a central role in limiting host immune response to pathogens, thereby preventing damage to the host and maintaining normal tissue homeostasis.

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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Systemic sclerosis often disfigures the most visible parts of the body (e.g., face and hands), which may alter a patient’s self-image, leading to body image dissatisfaction and reducing the individual’s quality of life (Del Rosso et al., 2013). In systemic sclerosis, depression and anxiety are found to be related to a reduction in work ability, social activity, and capacity to respond to stressors and to higher levels of helplessness, pain, fatigue, social support, emotional focused coping, and fear of disease progression (Kwakkenbos et al., 2015; Thombs et al., 2008). Depressive symptoms in systemic sclerosis have also been found to be linked to pulmonary restrictive disease, fatigue, and other physical symptoms (Del Rosso et al., 2013). In a study by Roca et al. (1996) it was found that depression in systemic sclerosis was correlated with higher levels of functional disability. In a more recent study, Del Rosso and colleagues (2013) found that depression and anxiety in systemic sclerosis patients were associated with a decreased quality of life, decreased sexual functioning, nonadherence to treatment, and increased requests for health care. The authors also found that depressive symptoms were significantly correlated with overall disability, hand and mouth disability, fatigue, low self-esteem, and avoidance strategy in coping (Del Rosso et al., 2013).

Depression and anxiety are also common mental health problems in people with pSS. Research examining patients with pSS compared to patients with RA and to healthy controls found that patients with pSS had higher rates of anxiety and depression than both of the other groups (Valtýsdóttir et al., 2000). In a cross-sectional study of 107 female patients with pSS, anxiety and depression were significantly related to poorer measures of health-related quality of life (Inal et al., 2010). Other studies (Milic et al., 2019) have found higher rates of anxiety in patients with pSS than in healthy controls and, in particular, have found anxiety to be even more common than depression in patients with pSS—specifically those who present with sicca symptoms (Milin et al., 2016).

Research is limited on mental health in patients with myositis, including polymyositis and dermatomyositis. One cross-sectional study sought to characterize anxiety and depression in patients with dermatomyositis (N = 41, mean age = 58.9) and to identify unmet needs for mental health services (Achtman et al., 2016). The researchers found that 44 percent of patients met criteria for depression or anxiety, based on standardized assessments (PHQ-9 and GAD-72, respectively). Of those patients, 33 percent were not receiving any mental health care even though the levels of depression and anxiety identified on the assessment tools signified that a need for mental health care was present.

It is important to acknowledge the role of depression and anxiety in rheumatic diseases and the synergistic impact on functioning of having both

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2 PHQ-9 = Patient Health Questionnaire-9; GAD-7 = General Anxiety Disorder-7.

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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a rheumatic disease and a mental health condition. Given the uncertainty of flares and disease prognosis and the lack of effective curative treatments, anxiety may be a common response to the stress of living with concerns about disease progression or becoming disabled (Aundhia et al., 2020; Beşirli et al., 2020). Chronic pain related to rheumatic diseases also may exacerbate depression and anxiety (Lewin et al., 2020). Adjusting to a new diagnosis of a rheumatic disease may lead to clinically significant feelings of depression or anxiety that affect function for up to 6 months but that may not meet the criteria for a major depressive or anxiety disorder (Fragoulis et al., 2020).

Clinical diagnosis of adjustment disorders is time-limited, by definition. However, they may affect a person’s ability to carry out functional activities during that time of adjusting to a new or worsening situation. All such psychiatric diagnoses, in concert with the rheumatic disease, should be considered when determining functional status. Another consideration is that some symptoms of psychiatric conditions may resemble symptoms of a rheumatic disease. For example, fatigue, weakness (i.e., psychomotor slowing), sleep dysfunction, and low appetite may contribute to depression or to the effects of inflammation from the underlying autoimmune condition, all of which may contribute to functional impairments.

PAIN

Pain is a primary feature across most immune system disorders, and for some conditions it is a defining diagnostic criterion. The International Association for the Study of Pain states that pain is a personal and subjective phenomenon defined as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” (Raja et al., 2020, p. 1976).

Chronic pain is defined as pain that persists or recurs for more than 3 months (Treede et al., 2019), and prevalence estimates for chronic pain in the United States range from 11 percent to 40 percent. Chronic pain, a leading cause of disability in the United States, contributes to high health care costs and is frequently a cause of restricted mobility, impairments in quality of life, and decrements in psychological health (IOM, 2011). Chronic pain is best understood as a multifactorial experience that affects and is affected by multiple domains of function. Chronic and recurrent pain is particularly relevant in immune system diseases and may act as a driving force for functional impairment and disability.

Important to the discussion of immunologic and rheumatologic conditions is the classification of chronic pain syndromes. Chronic pain has been classified into subcategories of primary chronic pain syndromes (i.e., a chronic pain condition existing as a disease in its own right) and secondary

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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chronic pain (i.e., a chronic pain syndrome that is linked to another disease), both of which can be present in individuals with immunologic conditions (Treede et al., 2019). Furthermore, pain can originate from three different sources: (1) nociceptive pain caused by inflammation or tissue damage, (2) neuropathic pain resulting from nerve damage or dysfunction, and (3) nociplastic pain originating from heightened central nervous system reactivity and sensory processing (Minhas and Clauw, 2021). Thus, the cause for impairments in function for those with immunologic diseases is not limited to the disease process itself, nor is it limited to pain that arises directly from the disease process. Chronic pain in immunologic conditions can stem from all three sources.

In rheumatoid arthritis, pain is considered a primary feature of the disease, particularly in those experiencing a flare in symptoms (Iver and Lee, 2021). Traditionally, it has been assumed that pain in RA is primarily due to peripheral joint inflammation; however, central pain mechanisms have also been found to play an important role. Peripheral joint pain may be due to inflammation in the large and small joints, which also causes morning stiffness, or it may be due to damage and destruction of the joints or to some combination of inflammation and damage, although numerous other factors have been identified that can also contribute to the pain (e.g., emotional factors, sleep) (Lampa, 2019). Because of the multiple factors that can lead to joint pain, a patient with, for example, well-controlled inflammation may still experience chronic pain due to joint destruction. And even in those with well-controlled or mild RA, the patients can still present with debilitating symptoms of primary chronic pain syndromes due to the centralized pain process that is common in this population (Woolf, 2011).

Pain in SLE can have a significant impact on a patient’s quality of life (Pisetsky et al., 2021). Pain in SLE may stem from the musculoskeletal system, neuropathic/neuropsychological sources, or serositis (inflammation of the membrane lining the lungs, heart, and abdomen). Musculoskeletal pain in SLE can stem from arthritis, myositis, avascular necrosis, fracture, osteoarthritis, or fibromyalgia. Neuropathic pain, such as small fiber neuropathy, and neurological pain, such as headaches or migraines, can also affect patients with SLE. In fact, headaches or migraines have been reported in a majority of SLE patients (Glanz et al., 2001). Serositis, such as pericarditis or pleuritis, can present with severe pain and inflammation and may be indicative of acute problems in need of emergent medical attention. Other painful manifestations include vasculitis and the side effects of medications (e.g., pancreatitis from steroids or nonsteroidal anti-inflammatory drugs [NSAIDs]).

Pain affects 62 percent to 83 percent of patients with systemic sclerosis (Benrud-Larson et al., 2002; Carreira, 2006; Merz et al., 2017). Manifestations include pain from digital ulcers (which can lead to chronic pain and functional impairment), joint inflammation, contractures, tendonitis,

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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and gastrointestinal disorders (Guillevin et al., 2013). In Sjögren’s syndrome, pain is also common and may arise from arthritis, arthralgia, or neuropathic pain such as small fiber neuropathy (Lampa, 2019).

The work of the international Myositis Working Group of Outcome Measures in Rheumatology (OMERACT) showed that health care providers are traditionally taught that myositis is typically painless (Alexanderson et al., 2014). However, there is now widespread acknowledgement, based on myositis patient focus groups, that patients do indeed experience a significant amount of pain. Focus groups conducted by Regardt and colleagues (2015) found that participants emphasized “their experience of pain, stiffness and discomfort, fatigue, insomnia, symptom variations, and cognitive dysfunction, as well as limitations in daily activities and participation in society.” In a survey of 643 myositis patients at the 2016 International Consensus Conference on Outcome Measures in Rheumatology, Park and colleagues (2017) found that the top five most important domains from the patient perspective were: muscle symptoms, fatigue, interactions with health care, medication side effects, and pain. Pain in myositis may occur in the muscles, skin, or joints, all of which are immunologic organ targets in myositis (Ponyi et al., 2005).

Treatment of pain in the setting of rheumatologic conditions typically begins with NSAIDs and disease-modifying anti-rheumatic drugs (DMARDs) for the purposes of decreasing inflammation and managing the underlying disease process that may be the cause of the pain. In managing chronic pain, treatment is best approached from a biopsychosocial perspective. Specifically, chronic pain can be a symptom of an underlying health condition (i.e., rheumatic disease) or a primary condition in itself, and interacting biological, psychological, and social factors may contribute to the etiology, clinical course, and functional outcomes of all chronic pain conditions, regardless of their primary or secondary nature (IOM, 2011). Approaches that are narrowly focused on relieving symptoms, such as analgesic medications, often fail to restore functioning or to provide long-term pain relief. In chronic pain, opioid analgesics lack demonstrated advantages over other treatments and are associated with increased disability and reduced functional recovery; although they are commonly prescribed, opioids are not recommended in chronic pain guidelines (NASEM, 2020).

The experience of pain is highly variable among persons with similar anatomical findings or disease severity, even in well-described chronic pain conditions. Therefore, the treatment of chronic pain is also highly individualized, although it generally involves a combination of therapies aimed at alleviating symptoms plus therapies that target functional improvement as their goal. Biomedical approaches are necessary in the treatment of rheumatic diseases to ensure that the underlying disease and its clinical manifestations (e.g., pain, fatigue) are controlled as well as possible, including

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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with the use of medications of different classes, surgeries, assistive devices, and physical and occupational therapies. Non-pharmacologic approaches are an integral part in the management of chronic pain, both within and outside of rheumatic diseases. Exercise and cognitive behavioral therapy are core aspects of treatment and should be recommended for any patient with a rheumatic disease who is also suffering from chronic pain. The best treatment is an integrated multimodal approach that combines different types of therapeutic approaches to address medical, psychologic, and social factors in a coordinated and supportive fashion.

FIBROMYALGIA AND CENTRALIZED PAIN SYNDROMES

Fibromyalgia3 is a chronic pain condition characterized by central nervous system pain processing (i.e., centralized pain state) that leads to widespread and diffuse musculoskeletal pain as well as problems with sleep, fatigue, memory and mood (Clauw, 2014). It affects both adults and children (Weiss et al., 2019). Fibromyalgia is a critical topic in the discussion of rheumatic diseases, given the high prevalence of primary chronic pain syndromes in this population. Fibromyalgia affects 10–30 percent of patients with rheumatic diseases such as RA and lupus (Clauw, 2014). This is significantly higher than the prevalence in the general population, which ranges from 2 percent to 8 percent, depending on diagnostic criteria used (McBeth and Jones, 2007; Vincent et al., 2013; Wolfe et al., 1995). Juvenile fibromyalgia has been found in 9 percent of patients with juvenile idiopathic arthritis (JIA) (Tesher et al., 2021). Although previously considered “secondary” in those with rheumatic diseases, it is important to understand fibromyalgia as a primary chronic pain condition in its own right, which can cause impairment in function across domains.

Classification criteria for fibromyalgia were developed in 1990 for research purposes and updated in 2011 and have been commonly used as a diagnostic tool in clinical practice (Wolfe and Häuser, 2011; Wolfe et al., 1990). The 1990 criteria required widespread pain (axial skeleton above and below the waist on both left and right side) as well as a positive exam on 11 out of 18 tender points. The 2011 revision recommends a self-report survey that evaluates pain location as well as presence of fatigue, sleep disturbance, memory difficulties, headaches, abdominal pain, and depression (Wolfe and Häuser, 2011). The latter assessment does not require a tender-point examination. In clinical practice, including the practice of rheumatologists

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3 Several terms are used to characterize centralized pain states such as fibromyalgia. They include: centralized pain, pain amplification syndrome, amplified musculoskeletal pain, central sensitization, widespread [musculoskeletal] pain, nociplastic pain, and generalized pain (Clauw, 2014; Lampa, 2019).

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
×

treating primary rheumatic diseases, fibromyalgia should be suspected or at least assessed when a patient presents with multifocal pain that is not fully explained by inflammation or the patient’s disease process. Clinical diagnosis in juvenile fibromyalgia involves a detailed history and physical examination, including a thorough neurological examination. Because juvenile fibromyalgia is under-recognized by health care providers, delays in diagnosis from 6 months to 5 years are not uncommon (Coles et al., 2021).

The defining characteristics of fibromyalgia include diffuse or multifocal musculoskeletal pain that often waxes and wanes and frequently migrates to different locations throughout the body (Clauw, 2014). The quality of the pain can also be described as neuropathic (patients use terms such as numbness, tingling, burning) to describe paresthesias and dysesthesia. Tenderness or sensitivity to touch or clothing may also be present. Patients often have had a history of pain in other body sites earlier in life. Accompanying symptoms include pain in other locations (e.g., headaches, abdomen) and sensory hyperresponsiveness (i.e., sensitivity to bright lights, loud noises). In addition, individuals with fibromyalgia typically report fatigue as well as disturbances in sleep, mood, and cognition (i.e., memory).

Risk factors related to the onset of fibromyalgia include family history (Arnold et al., 2004), genetics (Holliday and McBeth, 2011; Kato et al., 2009; Wolfe et al., 2011), certain types of infections (Buskila et al., 2008), and environmental factors such as acute pain episodes, physical or psychological trauma (McLean et al., 2011), deployment to war (Lewis et al., 2012), and stress (Clauw, 2014). Importantly, having a diagnosis of a rheumatic condition or other chronic pain condition (Phillips and Clauw, 2013) is also a risk factor in the development of fibromyalgia. Although different assessment tools have been used to diagnose fibromyalgia, research suggests that 22.1 percent of patients with RA meet the diagnostic criteria for fibromyalgia (Perrot et al., 2017). Other estimates suggest that 18 to 24 percent of patients with inflammatory arthritis meet the criteria for fibromyalgia (Lampa, 2019; Winthrop et al., 2019). In a study using the National Databank for Rheumatic Diseases, researchers found that 22.1 percent of patients with SLE met the criteria for fibromyalgia and 17 percent of patients with RA did (Middleton et al., 1994; Wolfe et al., 2009). Comorbid fibromyalgia, often underdiagnosed in lupus, can be identified using screening questionnaires to supplement traditional patient history and examination (Huang et al., 2020). There are no population-based studies of prevalence of fibromyalgia in systemic sclerosis, although one study that used several different screening questionnaires for fibromyalgia estimated the prevalence to be 27.8 percent (Perrot et al., 2017). Comorbid fibromyalgia in spondyloarthropathy has been reported in several studies (Lampa, 2019; Perrot et al., 2017; Wach et al., 2016) with a prevalence of 17.5 percent. Its

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
×

co-occurrence was higher in peripheral spondyloarthritis (27.3 percent) than in axial spondyloarthritis (14.8 percent), when assessed separately. A high prevalence of fibromyalgia has also been reported to occur in polymyositis, although it may exist with higher frequency in women than in men (de Souza et al., 2011). Taken together, those data suggest that patients across a variety of rheumatic diseases are likely to present with fibromyalgia.

Fibromyalgia has the potential to cause extensive functional disability and the inability to perform daily and work-related activities, resulting in a significant economic impact in terms of work absenteeism, decreased work productivity, disability and injury compensation, and overuse of health care resources (Hackshaw, 2020; Schweiger et al., 2017). The complexity and heterogeneity of the symptoms of fibromyalgia require a multidimensional approach to evaluation in order to identify the different etiological domains of the disability. For example, pain intensity affects physical, emotional, social, and work functionality as well as rates of unemployment (Ben-Yosef et al., 2020).

Worldwide, unemployment rates due to fibromyalgia range from 34 percent to 77 percent depending on location-specific social beneficiary systems, the labor market demands of different countries, and the varying definitions of work (Henriksson et al., 2005; Schweiger et al., 2017). In the United States, a study of over 700,000 employees from large self-insured employers enrolled in the Human Capital Management Services Research Reference Database from 2001 to 2008 found the prevalence of fibromyalgia to be 0.73 percent among those enrolled in a health plan for at least a year (2,959 employees) (Kleinman et al., 2009). Annual employer health benefits costs for these patients were $8,452 per employee adjusted for age, gender, region, Charlson comorbidity index, marital status, salary and year, as compared with $4,013 per employee for non-fibromyalgia controls (Kleinman et al., 2009). The likelihood of an emergency department visit was 16 percent for employees with fibromyalgia versus 6 percent for non-fibromyalgia controls per year, adjusted for these same factors. Employees with fibromyalgia were admitted to the hospital at a rate of 10 percent compared to 4 percent annually for controls, and used significantly more sick leave days than those without fibromyalgia (17 versus 6 days) per year (Kleinman et al., 2009). Although symptoms affecting work disability vary, employees with fibromyalgia have reported the symptoms limiting work to be pain, fatigue, muscle weakness, and memory and concentration difficulties. Symptom severity was found to influence work ability, with physically demanding jobs being especially affected and with workers in those jobs having a higher risk of work disability (Palstam and Mannerkorpi, 2017). Most often, individual adjustments in the work situation are made, and when individuals find a work situation that matches their ability, they continue to work and find satisfaction in their work

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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role. It is important to consider that many factors other than the degree of impairment influence the ability to remain in the workforce, including other commitments, the types of work tasks, the physical and psychosocial work environment, and the economy. When done carefully, adjustment in the workplace can prevent many episodes of sick leave, particularly the longer absences, resulting in greater productivity and employee satisfaction (Palstam and Mannerkorpi, 2017).

Studies report severe pain and functional limitations in children with juvenile fibromyalgia. In a study of 7,753 patients enrolled in a multinational registry, functional measures and well-being rated significantly worse in patients with juvenile fibromyalgia compared to patients with other rheumatic diseases (Connelly and Weiss, 2019). In a study of patients with JIA, those who also met the criteria for juvenile fibromyalgia showed much worse functional disability, measured using the Functional Disability Inventory, a self-report questionnaire that assesses perceived difficulty in performing daily activities in home, school, recreational, and social domains (Tesher et al., 2021).

The treatment of fibromyalgia combines pharmacologic and non-pharmacologic modalities. Commonly prescribed pharmacologic agents include tricyclic antidepressants (amitriptyline, nortriptilyne), gabapentinoids (gabapentin, pregabalin), serotonin–norepinephrine reuptake inhibitors (duloxetine, venlafaxine), muscle relaxants (cyclobenzaprine), and low-dose naltrexone. Opioids have not been shown to be effective in the treatment of centralized pain conditions such as fibromyalgia. Medications typically used to treat peripherally mediated pain in patients with rheumatic diseases, such as NSAIDs and corticosteroids, do not generally treat pain from fibromyalgia effectively (Clauw, 2010). Patients with RA and symptoms consistent with fibromyalgia have been shown to be treated more frequently with biologic therapies (Lage-Hanson et al., 2016), although those therapies are not designed to target the mechanism of action in centralized pain and presumably do not help decrease the pain associated with fibromyalgia. Thus for patients with a presentation of a rheumatic disease and additional fibromyalgia, it is often necessary to use a combination of several medications that have different mechanisms of action to treat both the patient’s rheumatic condition and the fibromyalgia.

Non-pharmacologic treatments for fibromyalgia are often more effective at improving patients’ function than pharmacologic approaches (Goldenberg et al., 2004; Williams et al., 2002). Specifically, pain education, graded aerobic exercise, and cognitive behavioral therapy all have strong evidence for efficacy in the treatment of fibromyalgia. Complementary and alternative medicine approaches can also be beneficial adjunctive therapies, including yoga, acupuncture, trigger point injections, tai chi, chiropractic care, and myofascial release therapy (Mist et al., 2013).

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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FATIGUE

Severe fatigue is reported by a large portion of people with immune disorders. Most research on fatigue in immune disorders has been studied in RA, where estimates of the prevalence of fatigue range from approximately 40 percent to as high as 70 percent (Hewlett et al., 2011a), although similar rates have been reported in other immune disorders (Arnaud et al., 2019; Esbensen et al., 2020). Specifically, it has been reported that 41 percent of individuals with RA (Overman et al., 2016; Thombs et al., 2008); 52 percent of individuals with SLE (Overman et al., 2016; Thombs et al., 2008); 51 percent with psoriatic arthritis (Overman et al., 2016); 48 percent with scleroderma (Overman et al., 2016; Thombs et al., 2008), and 60–70 percent with Sjögren’s syndrome (Pertovaara and Korpela, 2019) experience severe fatigue (Overman et al., 2016). Severe fatigue is also common in pediatric immune disorders; for example, a systematic review found that 60–76 percent of patients with JIA reported fatigue (Armbrust et al., 2016). In addition, comorbid fibromyalgia may be an underappreciated cause of fatigue, and an estimated 82 percent of individuals with fibromyalgia experience fatigue (Overman et al., 2016). In patients with pediatric rheumatic diseases, fatigue is associated with increased pain and decreased quality of life (Nijhof et al., 2016).

Fatigue in those conditions is experienced as different from “normal” tiredness (Hewlett et al., 2005) and is viewed by patients as overwhelming, uncontrollable, and, often, untreatable (Repping-Wuts et al., 2008). For example, in a survey of 274 patients with RA, 67 percent of respondents reported that an important characteristic of a period of remission is reduced fatigue (van Tuyl et al., 2017). In another study, 57 percent of RA patients said that a day free of fatigue, or a day in which they had energy, was one of the main indicators of a “good day” (58 percent also listed being pain-free as a main indicator) (Strand et al., 2015). Individuals with other immune disorders define fatigue as their greatest problem and the most difficult symptom to address (Basta et al., 2018; Morgan et al., 2014; Raymond et al., 2021; Seror et al., 2011).

The impact of fatigue is significant. Fatigue decreases one’s ability to function and to carry out daily activities (Conaghan et al., 2020; Repping-Wuts et al., 2008). It can affect mood, diminish social participation and functioning, and reduce the quality of life overall (Conaghan et al., 2020; Miyamoto et al., 2019; Murphy et al., 2021; Strand et al., 2020). As examples, individuals with RA report that it influences everyday tasks, attitudes, and leisure time. Fatigue among persons with RA is associated with declines in functioning, worse mental health status, higher levels of interpersonal stress, and greater health care use (Nikolaus et al., 2013). It can make management of other RA symptoms more challenging and interfere with

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
×

participation in rehabilitation (Belza and Dewing, 2006). Patients view RA fatigue as unpredictable and interfering with participation in all types of life activities (Minnock et al., 2017). In a study asking patients to define remission, a reduction in or the absence of fatigue was rated as essential by 41 percent of respondents, behind only improvements in pain (60 percent) and physical functioning (51 percent) (van Tuyl et al., 2017).

Perhaps the biggest question about fatigue in immune disorders is its etiology. Disease-specific factors do appear to be related to fatigue, as do some of the overlapping manifestations, such as pain, stiffness, and functional limitations. Clinical measures of disease activity and also biomarkers, including specific cytokines, antibodies, and gene expression profiles, have been linked to fatigue in a number of immune disorders (Bodewes et al., 2019; Evers et al., 2013; Karshikoff et al., 2017; Morris et al., 2016; Pertovaara and Korpela, 2019; Schwarting et al., 2019). Studies generally show a direct link between pain and fatigue (Basta et al., 2018; Madsen et al., 2016; Nikolaus et al., 2013; Walsh and McWilliams, 2014). Fatigue is higher among individuals with greater functional limitations (Grøn et al., 2014; Nikolaus et al., 2013). Functional impairments may decrease the efficiency of movement, requiring more energy or the use of less developed muscles to avoid pain (Belza and Dewing, 2006). Joint deformities or swelling may increase the work required for specific activities (Hewlett et al., 2005). However, those findings are inconsistent, and even when associations are found, clinical and biological factors account for only a modest amount of the variability in fatigue (Druce et al., 2015; Madsen et al., 2016; Miyamoto et al., 2019; Nikolaus et al., 2013; van Steenbergen et al., 2015). People whose disease is well controlled can have still have significant levels of fatigue (Olsen et al., 2016).

Multimorbidity is one factor that has been implicated in RA fatigue (Davis et al., 2020), but little study has been conducted in other immune disorders. Some forms of anemia, particularly anemia of chronic disease caused by chronic inflammation and acute hemolytic anemia, are frequent in immune disorders and are another potential source of fatigue (Aringer, 2020; Bowman, 2002; Klein and Molad, 2021; Vivino, 2017; Wilson et al., 2004). Fatigue is also a common symptom of hypothyroidism. A number of studies have found an elevated prevalence of hypothyroidism or other thyroid disease in individuals with immune disorders (Alfaris et al., 2010; Antonelli et al., 2017; Fallahi et al., 2016, 2017; Singh et al., 2014; Watad et al., 2016).

Effective treatments for fatigue appear to be limited. Medications used to treat immune disorders seem to have limited effects on reducing fatigue (Almeida et al., 2016; Chauffier et al., 2012; Conaghan et al., 2020; Druce et al., 2016a,b; Mertz et al., 2020; Miyamoto et al., 2019). A systematic review and meta-analysis found that the effects of biotherapies on fatigue

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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in RA are small (Chauffier et al., 2012). Most patients reaching disease remission after anti-tumor necrosis factor therapy continue to report fatigue (Conaghan et al., 2020; Druce et al., 2016a; Jorgensen et al., 2021; Strand et al., 2020).

Trials of programs focused on managing thoughts concerning fatigue have demonstrated improvements in fatigue (Cramp et al., 2013; Dures et al., 2012). Programs using such approaches as cognitive behavioral therapy appear to have a positive impact (Hewlett et al., 2011b), but the likelihood of such programs becoming widely available is unknown because of the resources required for them. Two recent systematic reviews found that physical activity had beneficial effects on fatigue (Cramp et al., 2013; Rongen-van Dartel et al., 2015). Recently tested exercise interventions specifically targeting RA fatigue have shown promising effects (Durcan et al., 2014; Feldthusen et al., 2016; Katz et al., 2018), but they have not been tested in other immune disorders. The challenge lies in identifying interventions that are both effective and feasible for widespread dissemination.

Fatigability vs. Fatigue

The concept of “fatigability” is distinct from fatigue. Fatigability has been defined as the susceptibility to experiencing fatigue in response to demand because of reduced physical capacity (Eldadah, 2010). Individuals who are more fatigable reach a level of perceived fatigue at a much lower demand. Reduced physical capacity may be due to a reduction or alterations in oxygen uptake and use or to changes in muscle function or strength (Marrelli et al., 2018). Reduced capacity (i.e., high fatigability) may contribute to high levels of fatigue. It may also contribute to the common occurrence of delayed recovery or greater disease activity after a period of overexertion.

Changes in muscle function and quality have been documented in RA, with the studies primarily focused on cachexia, or an accelerated loss of lean muscle mass (Giles et al., 2008). Cachexia appears to be driven by the excess of pro-inflammatory cytokines involved in RA. Dysfunction in skeletal muscle function (e.g., mitochondrial dysfunction) has been found in both RA and lupus (Chung et al., 2019; Marrelli et al., 2018; Steinz et al., 2020). The lupus study also found delayed recovery from an exercise stimulus. Other studies have linked specific aspects of muscle dysfunction, including fatigability, to higher circulating levels of interleukin (IL)-6 (Huffman et al., 2021; Vanderveen et al., 2019), a cytokine that is implicated in a number of autoimmune diseases. The usual approach to treatment is to reduce RA disease activity as much as possible, followed by a gradual increase in physical activity.

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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COGNITIVE FUNCTION

Cognitive function includes orientation, attention/concentration, judgment/problem solving, memory, verbal, visual/spatial, and executive functions (Meade et al., 2018). Among autoimmune disorders, cognitive functioning has received the most attention in SLE. However, recent evidence also points to cognitive dysfunction in other autoimmune disorders.

Cognitive impairment can have a significant impact on an individual’s daily functioning and quality of life. Even mild impairment can disrupt daily functioning (Julian et al., 2012). It may affect one’s ability to adhere to treatments and self-care. Cognitive impairment is also associated with an increased risk of disability, including work disability (NASEM, 2019).

The American College of Rheumatology defines cognitive impairment in SLE as significantly deficient functioning in at least one of the following domains: simple or complex attention, learning and memory, visuospatial processing, psychomotor speed, verbal fluency, reasoning ability, problem solving, or the executive processes of planning, organization, and sequencing (Kozora et al., 2004, 2008). The estimates of cognitive impairment in SLE vary widely, from 4 to 88 percent of adults with lupus and 33 percent of children with lupus, depending on the measures used and the criteria for defining impairment (Al Rayes et al., 2018; Hanly et al., 2019; Santos et al., 2021). While cognitive impairment is considered a neuropsychiatric manifestation of SLE, cognitive deficits can be present relative to controls or age-based norms even without the presence of overt neuropsychiatric symptoms (Leslie and Crowe, 2018). Among the deficits often noted are decreased attention and impairment in working memory and executive function (Hanly et al., 2010; Leslie and Crowe, 2018). Cognitive impairment in SLE has been attributed to both ischemic and inflammatory pathways and linked to a variety of inflammatory substances and autoantibodies and to complement activation (Hanly et al., 2019; Schwartz et al., 2019). Changes in brain structure have been noted in some studies, although these findings are not consistent (Hanly et al., 2019; Kozora and Filley, 2011; Kozora et al., 2011, 2012).

Neuropsychological impairment is not usually associated with RA, but recent studies suggest that there may be a link between RA and cognitive impairment (Meade et al., 2018; Vitturi et al., 2019). A recent review concluded that people with RA significantly underperformed compared with controls or aged-based norms on tests of verbal function, memory, and attention, with an estimated prevalence of impairment ranging from 38 to 71 percent (Meade et al., 2018). A constellation of clinical and psychological factors may be associated with cognitive impairment in RA, including cardiovascular disease, chronic pain, depression, and a range of autoimmune and inflammatory factors, along with changes in hormone levels and drug side effects, specifically glucocorticoids and methotrexate

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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(Basile et al., 2021; Coluccia et al., 2008; Gorelick., 2010; Pamuk et al., 2013; Wallin et al., 2012). Notably, many of those factors are relevant to other immune disorders.

Cognitive function in adults with JIA was found in one study to be poorer than in matched controls and to be inversely associated with disease duration, inflammatory activity, and educational level (Mena-Vázquez et al., 2021). The deficits appeared to be concentrated in the visuospatial domain. However, another study showed no differences between children and adolescents with JIA and controls (Feldman et al., 2005). There is some evidence of impaired cognition as measured with the Montreal Cognitive Assessment and compared with controls in both ankylosing spondylitis and psoriatic arthritis (Di Carlo et al., 2021; Vitturi et al., 2020). Abnormalities in systemic sclerosis are more commonly reported and are associated with duration of disease and disease severity as well as possibly with cerebral vascular compromise or disease-related autoantibodies (Giuliodori et al., 2009; Khedr et al., 2020; Yilmaz et al., 2012). Although studies are scarce and have small samples, cognitive dysfunction appears to be common in pSS, manifesting primarily as “brain fog” or mild cognitive impairment, and it is often the first clinical manifestation (Manzo et al., 2019; Riega-Torres et al., 2020).

There are differing levels of evidence regarding the prevalence of cognitive impairment in various immune disorders. For SLE, the body of evidence is strong and consistent. For RA, evidence showing an increased prevalence is accruing. For other immune disorders, evidence is sparse, but where it exists it tends to show increased rates of cognitive dysfunction. The proposed mechanisms of action are similar across conditions—inflammation, cardiovascular disease, and chronic pain (Basile et al., 2021; Gorelick, 2010; Hanly et al., 2019; Khedr et al., 2020; Oláh et al., 2020; Petersen et al., 2018; Wallin et al., 2012). Specific autoantibodies have been implicated in SLE and systemic sclerosis (Khedr et al., 2020; Schwartz et al., 2019). Medications that may be used across immune disorders are also implicated as contributors to cognitive dysfunction, specifically glucocorticoids and methotrexate (Coluccia et al., 2008; Pamuk et al., 2013).

TREATMENTS, SIDE EFFECTS, AND WHAT TREATMENTS INDICATE ABOUT DISEASE SEVERITY4

There are no current treatments known to cure immune disorders. Rather, treatment is used to reduce disease activity and thus prevent, or at least limit, organ damage (Shi et al., 2013). Glucocorticoids are used as a

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4 One of the items in the committee’s Statement of Task is: “What receipt of the treatments indicates about the severity of the medical condition.”

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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first-line therapy in many cases because of their global action on multiple inflammatory pathways and because of their rapid onset of action; they can be used concurrently with DMARDs (Barsotti and Lundberg, 2018; Both et al., 2017; Griger et al., 2017). Table 2-1 describes the common categories of drugs used to treat immune disorders, how they are used, examples of the drugs, and the potential side effects of these therapies. The disease-specific chapters will provide additional detail for drugs that are effective for each condition as well as experimental therapies that are in development.

Many of the drugs commonly used to treat immune disorders are considered off-label drugs. That does not mean that the drugs are “experimental.” Rather, off-label drugs are FDA-approved, but not approved to treat a specific immune disorder (FDA, 2018). The use of experimental drugs could be an indicator of disease severity, as patients might try experimental drugs when approved or off-label drugs are not working. The FDA’s Right to Try Act, signed into law May 30, 2018, allows patients with life-threatening diseases who have tried all approved treatment options and who are unable to participate in a clinical trial to access certain experimental treatments (FDA, 2020). Providers constantly assess the benefit-to-risk ratio of DMARD therapies with a primary goal of treating the underlying condition and minimizing the risk of side effects. Patients with refractory disease often have a history of inefficacy to several medications. Additionally, the use of intravenous (IV) glucocorticoids and cyclophosphamide may indicate acute and severe decompensation of a newly diagnosed or underlying immune disorder. Thus, combination therapy and the addition of drugs to treat multiple systemic effects may be indicators of more severe disease.

TREATMENT SETTINGS AND AVAILABILITY

Treatments for immune disorders are administered in a variety of settings including outpatient, inpatient, infusion center, and home infusion. Medications may be administered by the oral, subcutaneous, and IV routes. Some targeted biologic medications can be administered orally or subcutaneously by the patient at home, whereas other medications require IV infusion and may be administered in a hospital, infusion center, doctor’s office, or home setting with nurse supervision. IV cyclophosphamide and rituximab are almost always administered at an inpatient or at an infusion center as they have higher rates of infusion reactions than some other commonly administered IV medications and require monitoring. IV glucocorticoids are commonly administered along with other IV therapies. For acute flares in some of the immune disorders, intramuscular or intra-articular glucocorticoids may be administered in a physician’s office. Patients with moderate to severe disease or acute exacerbations may require treatment

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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TABLE 2-1 Common Therapies for Immune Disorders and their Potential Side Effects

Treatment category Usage and examples Side effects
Glucocorticoids Steroids are the first line of treatment in some circumstances where rapid control of inflammation is needed.
Most patients require additional immunosuppressive drugs to control disease activity and reduce the risks of glucocorticoid-related side effects.
Examples include prednisone, cortisone, and dexamethasone.
Side effects are common and include hyperglycemia, hypertension, dyslipidemia, osteoporosis, weight gain, skin thinning, gastric intolerance, mood changes, infections, hirsutism, cataracts, and glaucoma.
Conventional disease-modifying anti-rheumatic drugs (DMARDs) DMARDS are immunosuppressive drugs that are considered first-line therapy with or without steroids. Their initiation allows tapering of concurrent steroids. Examples include methotrexate, azathioprine, mycophenolates, cyclosporin, and cyclophosphamide. Potential adverse events with these medications include infections, cytopenias (especially with cyclophosphamide), hepatotoxicity (methotrexate, azathioprine), and renal impairment (cyclosporin).
Targeted DMARDs These include targeted biologic agents as well as targeted synthetic agents. Biologic agents include inhibitors of circulating cytokines such as tumor necrosis factor (TNF), interleukins-1, 6, 17 and 23 and interferon beta; inhibitors of B-cell growth factors and CD20–B-cell depleting therapies; and an inhibitor of T cell co-stimulation. Targeted synthetic agents include the janus kinase (JAK) inhibitors. The biologic agents are associated with injection and infusion reactions and increased risk of infections as well as additional drug-specific events. The JAK agents have been associated with cytopenias, increased risk of infection, and increased risk of thrombosis.
Nonsteroidal anti-inflammatory drugs (NSAIDs) NSAIDs are used to treat pain due to inflammation. Side effects include gastrointestinal (ulcers, dyspepsia), renal insufficiency, and increased risk of cardiovascular events, if taken chronically.

SOURCES: Barsotti and Lundberg, 2018; Both et al., 2107; Griger et al., 2017.

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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in a hospital or emergency department setting, which may indicate clinical severity.

In pediatric populations, most therapeutics are given orally or subcutaneously at home to minimize disruption for the child and family. Rarely are hospital admissions required for IV treatment. Where local infusion centers are unable to accommodate pediatric patients, inpatient hospitalizations for administration of IV drugs may be necessary.

The multisystem nature of immune disorders often requires management by multidisciplinary teams containing many specialties, including rheumatology, infectious disease, neurology, pulmonology, cardiology, gastroenterology, nephrology, dermatology, hematology, orthopedic surgery, transplant surgery, ophthalmology, dentistry, high-risk obstetrics, physical therapy, psychiatry, and pain management.

One consideration regarding treatment availability is related to the issue of prescribing off-label drugs or treatments for some of the immune disorders. That use of off-label medications limits their availability to patients because of insurance denial (for off-label use of medications). Additionally, regulatory issues prevent the use of some treatments because of the lack of established safety and efficacy.

Although treatment settings could provide some indication of disease severity, caution should be taken in making an association, as the availability of different types of medical care varies for different patients. Finally, there are documented workforce shortages in rheumatology. This shortage is particularly acute in pediatric rheumatology. It is not uncommon for patients to have to travel several hours to neighboring states or through several states to find a “local” rheumatologist, especially in the noncoastal U.S. states and the South (Miloslavsky and Bolster, 2020).

VARIABILITY OF DISEASE ACTIVITY AND FLARES

Many immune disorders are characterized by fluctuations in disease activity—periods of quiescence interrupted with periods of greater disease activity, or flares (Bingham et al., 2009; Christopher-Stine et al., 2020; Cooksey et al., 2010; Moverley et al., 2015). RA flares were defined by the OMERACT group as “a cluster of symptoms of sufficient duration and intensity that cannot be self-managed by the patient and require initiation, change or increase in therapy.” Operational definitions for flares in many immune disorders have been developed, with varying degrees of specificity, but the themes are consistent throughout (see Table 2-2). Flare activity may persist despite disease management.

Each episode of flare can lead to increased disease progression, functional impairment, and permanent organ or joint damage (Christopher-Stine et al., 2020; Cooksey et al., 2010; Markusse et al., 2015; Ugarte-Gil

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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TABLE 2-2 Themes Used in Definition of Flare

Themes Examples
Worsening of condition Worsening of disease activity/condition, a cluster of symptoms, new or worse signs, increase in disease activity
Change in treatment (Re)initiation or change (increase, change medication) of therapy, increase/add self-management
Pain Pain intensity, nocturnal pain/awakenings, DAS28
Symptom intensity Intensity of symptoms, overwhelming physical symptoms
Duration Duration, persistent, time to maximum pain level, time to complete resolution of pain, duration varying between days and weeks
Impact on function Function, participation, physical symptoms, changes in daily activity, Childhood Health Assessment Questionnaire
Joint symptoms Number of joints with active arthritis/limited range of motion, swollen/warm/tender/stiff/painful joints, DAS28
Patient self-reported state Self-reported flare, patient global assessment, parent and patient global assessment of overall well-being
Biomarkers Laboratory tests (e.g., ESR, CRP levels, acute phase marker)
Emotional symptoms Emotional/psychological changes/symptoms/consequences), health-related quality of life, coping, anger, depression, withdrawn
Physician assessment Physician global assessment
Fatigue Physical fatigue, emotional fatigue
Other Frequent, rare and random, manageable, flu-like symptoms/fever, muscle spasm, cramp, burning or tightness in the muscle, sweats, loss of appetite, grey pallor, shortness of breath, throughout the entire body

NOTE: DAS28 = Disease Activity Score 28, a measure of disease activity in rheumatoid arthritis that requires examination of 28 joints; ESR = erythrocyte sedimentation rate, a test that indirectly measures the degree of inflammation present in the body; CRP = C-reactive protein, a high test result is a sign of acute inflammation.

SOURCE: Reproduced from Costa et al., 2018, with permission.

et al., 2015). Further long-term complications can accrue due to toxicities from the medications (such as glucocorticoids) that are used to treat the flare.

Patients may experience fluctuations in disease that have noticeable effects on them yet are not persistent or severe enough to meet clinical or research definitions (Hewlett et al., 2012; Squance et al., 2014). The “bad days” are an indication of fluctuating disease activity and can be associated with increased disease progression, functional impairment, depression,

Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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diminished quality of life, and organ damage (Katz et al., 2020; Markusse et al., 2015; Moverley et al., 2015).

Some precipitating factors for flares have been identified; for instance, exposure to ultraviolet radiation and infections can be triggers for SLE flares. Patients often attribute flares to psychosocial stresses, overexertion, or environmental exposures (Squance et al., 2014). However, the causes of flares are generally unknown, which further contributes to the unpredictable nature of immune disorders.

COVID AND IMMUNE DISORDERS

There have been serious concerns about the vulnerability of individuals with immune disorders to COVID-19 infection, particularly regarding the possibility that immune disorders will make worse outcomes from COVID-19 more likely. Existing data suggest that people with immune disorders are not at higher risk of developing COVID-19 (Gianfrancesco et al., 2020a); however, a number of studies have shown that some subgroups with immune disorders may have a higher risk of hospitalization, admission to the intensive care unit, mechanical ventilation, and death from COVID-19 infection (D’Silva et al., 2021). Some of those increased risks can be attributed to comorbidities that also convey higher risk in the general population, such as obesity, diabetes, and chronic lung disease (D’Silva et al., 2021; Strangfeld et al., 2021). Glucocorticoid exposure ≥ 10 mg/day is associated with a higher risk of hospitalization and death (Gianfrancesco et al., 2020b; Strangfeld et al., 2021). High disease activity and the use of rituximab, sulfasalazine, and immunosuppressants such as cyclophosphamide or mycophenolate are also associated with a more severe disease course and higher odds of death (Bakasis et al., 2021; Strangfeld et al., 2021). Medium to high doses of steroids and severe immunosuppression are also high risk factors for hospitalization in children with pediatric rheumatic diseases (Villacis-Nunez et al., 2021). Recent advice from the Centers for Disease Control and Prevention (CDC) notes that people who are moderately to severely immunocompromised5 are especially vulnerable

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5 The CDC considers individuals to be moderately to severely immunocompromised if they meet any of the following conditions (CDC, 2022):

  • Been receiving active cancer treatment for tumors or cancers of the blood
  • Received an organ transplant and are taking medicine to suppress the immune system
  • Received a stem cell transplant within the last 2 years or are taking medicine to suppress the immune system
  • Moderate or severe primary immunodeficiency (such as DiGeorge syndrome, Wiskott-Aldrich syndrome)
  • Advanced or untreated HIV infection
  • Active treatment with high-dose corticosteroids or other drugs that may suppress your immune response
Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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to COVID-19. As a result, potential workplace exposures may constitute a greater risk for individuals with immune disorders, and it may be important to consider workplace or school accommodations.

A number of studies have demonstrated the significant impacts of the COVID-19 pandemic on mental health among various patients with immune disorders, including increases in depression, anxiety, sleep disturbance, and stress (Bhatia et al., 2021; Katz et al., 2020; Liew et al., 2020). Those effects on mental health also have been noted in the general population (McGinty et al., 2020). The unique risk in patients with immune disorders, however, is the possibility that those mental health challenges could lead to increases in disease flares or severity. While previous research suggests the feasibility of such occurrence, research has not adequately addressed the topic at this time. Reports from early in the pandemic also suggested the occurrence of dramatic reductions in routine medical care and increases in telemedicine, both in the general population and among patients with immune disorders specifically (Whaley et al., 2020). Whether that trend has reversed and whether there were differential effects in the health outcomes for people with immune disorders is not known at this time.

COVID-19 vaccines are generally recommended by the American College of Rheumatology for persons with immune disorders, although modification in the timing of some immunomodulatory therapies may be required (Curtis et al., 2021). There is emerging evidence that antibody production may be impaired by some immune therapies, particularly B-cell depleting therapies (e.g., rituximab) (Boyarsky et al., 2021; Ruddy et al., 2021). Thus, it is advisable to administer the vaccines prior to these B-cell depleting therapies to maximize antibody response.

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Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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Suggested Citation:"2 Cross-Cutting Issues." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
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The U.S. Social Security Administration (SSA) administers the Social Security Disability Insurance program and the Supplemental Security Income program. As part of their process, immune system disorders are evaluated under Listing of Impairments 14.00 for adults and 114.00 for children. At the request of the SSA, the National Academies of Sciences, Engineering, and Medicine assembled a committee to review selected conditions related to the immune system. In particular, the SSA was interested in the current status of the diagnosis, treatment, and prognosis of immune system disorders including systemic lupus erythematosus (SLE), scleroderma, polymyositis, Sjogren's syndrome/disease, and inflammatory arthritis.

This report provides an overview of the current status of the diagnosis, treatment, and prognosis of these immune system disorders in the U.S. population and the relative levels of functional limitation typically associated with them, common treatments, and other considerations.

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