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Selected Immune Disorders and Disability (2022)

Chapter: 3 Systemic Lupus Erythematosus

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Suggested Citation:"3 Systemic Lupus Erythematosus." 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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3

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease that produces a significant burden across different ethnic, racial, and age groups. It is a complex disorder of multifactorial etiology with an evolving pathophysiology. SLE leads to the impairment of several organ systems, including skin, musculoskeletal, renal, hematologic, cardiovascular, pulmonary, neuropsychiatric, and reproductive. SLE can have a broad range of clinical manifestations, a variable prognosis, and evolving clinical course, which is characterized by episodes of active disease and remission (Di Battista et al., 2018). The disease has several phenotypes, with varying clinical presentations ranging from mild mucocutaneous manifestations to multiorgan and severe central nervous system involvement. Despite recent advances in technology and the identification of several pathogenic autoantibodies, the pathological basis and risk factors for SLE are not well understood. The disease poses significant morbidity and mortality risk in patients (Vaillant et al., 2022).

SLE affects about 300,000 persons in the United States each year. It is 10 times more common in females than in males and 2 to 3 times as prevalent in black females as in white females (Pons-Estel et al., 2010). Over the past decade, the 5-year survival rate of SLE patients has improved to more than 95 percent due to more effective treatments of SLE’s infectious and renal complications (Lam et al., 2016).

A systematic review of the worldwide incidence and prevalence of SLE (Rees et al., 2017) found the highest estimates of incidence and prevalence to be in North America (23.2/100,000 person-years and 241/100,000, respectively). Women were more frequently affected than men for every

Suggested Citation:"3 Systemic Lupus Erythematosus." 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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age and ethnic group, with a female-to-male ratio of 9 to 1 (Fava and Petri, 2019; Izmirly et al., 2021). In individuals ages 15 to 44 years old, the female-to-male ratio increased to 13 to 1 (Fava and Petri, 2019). Women of childbearing ages are at greatest risk of developing SLE. About 20 percent of people with lupus developed the disease before 20 years of age. It is rare to get lupus before age 5 years. Lupus is also more common in certain ethnic groups, including African-American, Hispanic, South and Southeast Asian, and American Indian/Alaska Native populations (Izmirly et al., 2021; Stojan and Petri, 2018). People of African ethnicity had the highest incidence and prevalence of SLE, while Caucasians had the lowest incidence and prevalence. Additionally, the disease has an earlier age of onset and is more severe in African-Americans (Stojan and Petri, 2018).

This chapter will provide a brief overview of the clinical manifestations, disease course, and available therapeutic options for SLE as well as a discussion of functional limitations imposed by both the disease and its treatment.

CLINICAL FEATURES, DIAGNOSIS, AND DISEASE COURSE

Clinical Features

SLE is a multisystem disease with several phenotypes and clinical features that vary from mild (only skin and joint involvement) to severe, life-threatening disease (with multisystem involvement). All organ systems can be involved, and an autoantibody profile can be helpful in predicting the disease course and outcomes. The typical patient is a young woman of childbearing age, presenting with nonspecific constitutional symptoms, skin rash and joint pain. Nonspecific symptoms (e.g., fatigue, malaise, fever, anorexia, and weight loss) are seen in more than 90 percent of patients, whereas mucocutaneous or musculoskeletal manifestations, or both, are seen in more than 80 percent of patients.

Mucocutaneous Manifestations

The most frequently seen skin lesions include: acute cutaneous lupus erythematosus (ACLE), which can be localized, malar, or generalized (Figure 3-1, A, B, and C); subacute cutaneous lupus erythematosus (SCLE) (Figure 3-2), which can be annular or papulosquamous; and classic discoid lupus erythematosus (DLE), one form of chronic cutaneous lupus erythematosus (CCLE). Discoid lupus can result in permanent scarring and alopecia (Figure 3-3). In general, CCLE, which also includes hypertrophic/verrucous DLE, lupus panniculitis/profundus, lupus tumidus, chilblains lupus, mucosal discoid lupus, and lichenoid discoid lupus, is less frequently associated with SLE. Additionally, oral and nasal ulcers are common in SLE

Suggested Citation:"3 Systemic Lupus Erythematosus." 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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Image
FIGURE 3-1 Acute cutaneous lupus erythematosus manifestations: (A) localized; (B) malar; and (C) generalized.
SOURCE: ACR, 2021, with permission.
Image
FIGURE 3-2 Subacute cutaneous lupus erythematosus.
SOURCE: ACR, 2021, with permission.

and are often painless. Photosensitivity is present in more than 90 percent of cases and is characterized by abnormal skin reaction on exposure to ultraviolet A/B or visible light (Vaillant et al., 2022). Other skin manifestations include alopecia, cutaneous vasculitis, livedo reticularis, and Raynaud’s phenomenon (Fava and Petri, 2019).

Musculoskeletal Manifestations

Musculoskeletal manifestations are seen in 80–90 percent of patients with SLE and may range from mild joint pain to severe arthritis. Lupus

Suggested Citation:"3 Systemic Lupus Erythematosus." 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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Image
FIGURE 3-3 Discoid lupus erythematosus.
SOURCE: ACR, 2021, with permission.

arthritis typically is symmetrical, affecting predominantly the small joints of the hands, knees, and wrists. The involvement of the tendons and joint capsules may lead to severe reducible deformities of the joints, especially of the hands, which is known as Jaccound’s arthropathy. Patients with SLE may have chronic joint pain and are at high risk for developing fibromyalgia (Vaillant et al., 2022).

Hematologic Manifestations

Hematologic and reticuloendothelial manifestations are also seen and anemia is present in more than 50 percent of patients with SLE. The cause of anemia is multifactorial, but it is most often associated with chronic inflammation. Iron deficiency anemia, a result of menorrhagia or increased gastrointestinal blood loss (caused by the use of nonsteroidal anti-inflammatory drugs, asprin, and oral anticoagulants), is also common. Up to 10 percent of patients with SLE may have autoimmune hemolytic anemia or other immune-mediated anemia (Giannouli et al., 2006). Additionally, patients with SLE are at high risk of having a positive antiphospholipid antibodies (APLA)1 test as well as an APLA-related clinical outcome (thrombosis or pregnancy-related morbidity). About 50 to 70 percent of the patients with SLE and positive APLA progress to antiphospholipid syndrome (APLS)2 (Bustamante et al., 2021).

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1 Antiphospholipid antibodies (APLAs) are autoantibodies that are directed against phospholipid-binding proteins.

2 Antiphospholipid syndrome (APLS) is characterized by the presence of antiphospholipid antibodies in the setting of thrombosis or pregnancy loss.

Suggested Citation:"3 Systemic Lupus Erythematosus." 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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Leukopenia and neutropenia are very common in active lupus, but rarely are white cell counts low enough to lead to infection. Counts may be lowered by medications (e.g., azathioprine or cyclophosphamide, as well as other drugs). Thrombocytopenia can be mild or severe; pancytopenia is also seen and may be associated with aplastic anemia or myelofibrosis. Soft nontender lymphadenopathy is common in SLE.

Renal Manifestations

Lupus nephritis (kidney inflammation) is a common complication of SLE, occurring in up to 50 percent of patients and often early in the course of the disease. It is three to four times more common in ethnic minority groups than in whites and is also likely to have more severe features in ethnic minority groups. Most patients who develop lupus nephritis do so within 5 years of an SLE diagnosis. Lupus nephritis is a substantial cause of morbidity and death among patients with SLE. It may be characterized by hypertension, hematuria, proteinuria, lower extremity edema, and elevated creatinine, and it can cause significant morbidity. Lupus nephritis can be diagnosed on clinical assessment, but renal biopsies are often done to confirm this diagnosis and to categorize the histopathological nature of the inflammation. There are six classes (I-VI) of lupus nephritis based on histologic subtype and associated with clinical and serological features, although significant overlap occurs. Treatment is often guided by the histologic subtype. Class III (focal glomeruloproliferative), Class IV (diffuse glomeruloproliferative), and Class V (membranous) confer significant morbidity and mortality where untreated, and refractory cases can result in end stage renal disease (ESRD) and require renal replacement therapy. Black and Hispanic patients, males, and those with pediatric onset lupus or severe proteinuria (> 4g/24h) are at highest risk of progressing to ESRD (Rovin et al., 2019). Additional renal conditions that might be associated with SLE, and which may impair renal function, include thrombotic microangiopathy, interstitial nephritis, lupus vasculopathy, vasculitis, and arteriolosclerosis (Vaillant et al., 2022). Further, lupus nephritis has implications for disability, for example, the expectation of returning to work following dialysis.

Cardiopulmonary and Gastrointestinal Involvement

Serositis, or inflammation of the membrane lining the lungs, heart, and abdomen, is common in SLE, with the most frequent involvement of the pleura and pericardium. Pleuritis, a common pulmonary manifestation of SLE, is associated with chest pain and difficulty breathing. Other pulmonary complications include exudative pleural effusions, acute lupus pneumonitis, interstitial lung disease, diffuse alveolar hemorrhage associated with

Suggested Citation:"3 Systemic Lupus Erythematosus." 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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capillaritis, pulmonary hypertension, pulmonary embolism, and shrinking lung syndrome (Vaillant et al., 2022). Pericarditis, also associated with chest pain and difficulty breathing, is the most common cardiac manifestation of SLE, but lesions of the valves, myocardium, and coronary vessels may also occur (Doria et al., 2005).

Central Nervous System Involvement

Central and peripheral nervous systems may be involved in SLE, which also can include psychiatric manifestations. Intractable headaches, reported in more than 50 percent of cases, are the most common central nervous system manifestation. Focal or generalized seizures; aseptic meningitis; demyelinating syndrome, including optic neuritis and myelitis; and movement disorders also are seen. Furthermore, patients with SLE are at high risk for ischemic strokes, central and peripheral neuropathies, mononeuritis multiplex, and autonomic neuropathies. Peripheral nervous system manifestations include symptoms mimicking Guillain-Barre syndrome and myasthenia gravis. Patients may also experience debilitating fatigue and cognitive dysfunction (difficulty concentrating, poor memory), often referred to as “brain fog” (Al Rayes et al., 2018). Psychiatric manifestations are difficult to diagnose and may range from depression and anxiety to frank psychosis (Vaillant et al., 2022).

The table below (Table 3-1) summarizes the many possible manifestations of SLE.

Other Manifestations

In addition to the clinical features discussed above, there are many general presenting symptoms, including fever, malaise, arthralgias, myalgias, headache, and loss of appetite and weight. Nonspecific fatigue, fever, arthralgia, and weight changes are the most common symptoms in new cases or recurrent active SLE flares. Fatigue, the most common constitutional symptom associated with SLE, can be due to active SLE, medications, lifestyle habits, or concomitant fibromyalgia or affective disorders. Fatigue due to active SLE generally occurs in concert with other clinical and laboratory markers. A further discussion of fatigue in immune disorders can be found in Chapter 2. Fever, another common yet nonspecific symptom of SLE, may also result from many causes, the most common of which include active SLE, infection, and drug fever (Cojocaru et al., 2011).

Pregnancy complications are seen in patients with SLE, and there is a high risk of spontaneous abortion and fetal loss, pre-eclampsia, and

Suggested Citation:"3 Systemic Lupus Erythematosus." 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 3-1 Summary of Manifestations of Systemic Lupus Erythematosus

Physical manifestation Description Comments
Mucocutaneous Lupus specific lesions include: acute cutaneous lupus erythematosus (ACLE); subacute cutaneous lupus erythematosus (SCLE); chronic cutaneous lupus erythematosus (CCLE), which includes discoid lupus erythematosus (DLE), hypertrophic/verrucous, lupus panniculitis/profundus, lupus tumidus, chilblains lupus, mucosual discoid lupus, and lichenoid discoid lupus. More than 80% of patients with SLE suffer with mucocutaneous involvement.
Musculoskeletal Lupus arthritis is typically a nonerosive, symmetrical inflammatory polyarthritis affecting most often the small joints of the hands, knees, and wrists. There is high risk (20%) for the development of fibromyalgia, and rheumatoid nodules also have been reported. Approximately 80–90% of SLE patients will suffer from musculoskeletal involvement, ranging from mild arthralgias to deforming arthritis.
Hematologic Anemia due to chronic inflammation, iron deficiency, or immune mechanisms is common. Leukopenia secondary to neutropenia or lymphopenia is very frequent and can be severe. Thrombocytopenia can be mild or severe; pancytopenia also may occur and is associated with myelofibrosis. Soft nontender lymphadenopathy is common as is splenomegaly. More than 50% of patients have anemia.
Neuropsychiatric Both the central nervous system and the peripheral nervous system may be involved in SLE in addition to psychiatric manifestations. Focal or generalized seizures are associated with disease activity, as are aseptic meningitis, demyelinating syndrome, and movement disorders. Patients with SLE are at high risk for ischemic strokes. Cranial and peripheral neuropathies, mononeuritis multiplex, autonomic neuropathies, and syndromes mimicking Guillain-Barre syndrome and myasthenia gravis are the peripheral nervous system manifestations. More than 50% of patients report intractable headaches. Psychiatric manifestations are hard to diagnose and may range from depression and anxiety to frank psychosis.
Suggested Citation:"3 Systemic Lupus Erythematosus." 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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Physical manifestation Description Comments
Renal Lupus nephritis may range from mild subnephrotic proteinuria to diffuse progressive glomerulonephtitis leading to chronic kidney damage. A biopsy is critical in classifying lupus nephritis and ruling out other causes. Lupus nephritis is a common complication of SLE and usually occurs early in the course of the disease.
Pulmonary Other pulmonary manifestations include: exudative pleural effusions, acute lupus pneumonitis, interstitial lung disease, diffuse alveolar hemorrhage associated with capillaritis, pulmonary arterial hypertension, pulmonary embolism, and shrinking lung syndrome. Pleuritis is the most common pulmonary manifestation.
Cardiovascular Pericarditis associated with exudative pericardial effusions is the most common cardiac manifestation. Cardiac tamponade and myocarditis are rare. Valvular abnormalities, including Libman-Sacks endocarditis involving the mitral valve, are common. Patients with SLE are at high risk for coronary artery disease. Any layer of the heart may be involved, including pericardium, myocardium, endocardium, and coronary arteries.
Gastrointestinal Esophageal dysmotility, mesenteric vasculitis, lupus enteritis, peritonitis and ascites, protein-losing enteropathy, pancreatitis, and lupoid hepatitis are all manifestations of SLE. Any part of the gastrointestinal tract may be involved.
Eye/Ear Keratoconjunctivitis sicca is often seen in SLE. Other ocular manifestations include renal vasculitis, optic neuritis, uveitis, scleritis, peripheral ulcerative keratitis, and episcleritis. Ear involvement may lead to sudden sensorineural hearing loss. Eye involvement is common, and ear involvement may lead to sudden sensorineural hearing loss.
Pregnancy complications Patients with positive antiphospholipid antibodies are at high risk of spontaneous abortions and fetal loss, pre-eclampsia, and maternal thrombosis. SLE usually flares in pregnancy.

SOURCE: Summarized from Vaillant et al., 2022.

Suggested Citation:"3 Systemic Lupus Erythematosus." 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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maternal thrombosis. Anti-Ro/SSA and Anti-La/SSB3 antibodies are found in Sjögren’s syndrome, as well as other systemic autoimmune diseases, such as SLE, myositis, and scleroderma, and can cross the placental barrier and lead to fetal heart block and neonatal lupus; the risk is 2 percent with the first pregnancy but increases to 20 percent if there is a history of neonatal lupus in a previous pregnancy. SLE usually flares during pregnancy, especially if the disease was uncontrolled in the 6 months prior to the pregnancy. Patients with severe SLE manifestations such as pulmonary hypertension, APLS, cardiovascular disease, or cerebrovascular accidents are especially at very high risk of mortality during pregnancy (Vaillant et al., 2022).

Clinical Diagnosis and Professionally-Accepted Classification Criteria

Diagnosing SLE can be challenging as no single clinical feature or lab test can confirm the diagnosis. SLE is diagnosed based on the numerous signs and symptoms plus laboratory tests. Histopathology and imaging may also help in the diagnosis, as will specific autoantibodies. Antinuclear antibodies (ANAs) are the hallmark of the disease, and an immunofluorescence assay looking for them should be the initial test performed. Although a positive ANA is seen in more than 97 percent of cases of SLE, the specificity is poor (only 20 percent) and a positive result may also be seen in other disorders and in healthy populations (Valliant et al., 2022). Thus, a positive ANA should be followed by testing for more specific autoantibodies to detect the antigen responsible for the positive ANA (Valliant et al., 2022).

Classification criteria (see Fava and Petri, 2019) are used primarily for research purposes and should not be considered diagnostic criteria; however, they are listed in Table 3-2. Some patients with confirmed SLE will fail to meet the classification criteria, and the diagnosis of SLE should be made at the discretion of a rheumatologist. The current Social Security Administration (SSA) definitions refer to the 1997 update on the 1982 Revised Classification criteria for SLE,4 which has since been eclipsed by several classification criteria, with the SLICC (Systemic Lupus Erythematosus International Collaborating Clinics Group) criteria and the 2019 European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) criteria being the most commonly used. The 2019 EULAR/ACR classification criteria for SLE has a sensitivity of 96.1 percent and a specificity of 93.4 percent and is the most recent iteration. It requires

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3 Anti-SSA autoantibodies (anti–Sjögren’s-syndrome-related antigen A autoantibodies, also called anti-Ro, or similar names including anti-SSA/Ro, anti-Ro/SSA, anti–SS-A/Ro, and anti-Ro/SS-A) are a type of anti-nuclear autoantibodies that are associated with many autoimmune diseases.

4 See SSA Listing of Impairments, https://www.ssa.gov/disability/professionals/bluebook/14.00Immune-Adult.htm (accessed February 6, 2022).

Suggested Citation:"3 Systemic Lupus Erythematosus." 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 3-2 Updated European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) and Systemic Lupus International Collaborating Clinics (SLICC) Immunologic Criteria

SYSTEM 2019 EULAR/ACR CRITERIA SLICC CRITERIA
Immunologic Criteria
Antinuclear antibody (ANA)

Positive ANA result—entry criterion

(titer of ≥ 1:80 on HEp-2 cells or an equivalent positive test)

Positive ANA result
Other

SLE-specific antibodies (6 points)

Anti-dsDNA antibody

Anti-Smith antibody

Antiphospholipid antibodies (2 points)

Anti-cardiolipin antibodies or

Anti-β2GP1 antibodies or lupus anticoagulant complement proteins

Low C3 OR low C4 (3 points)

Low C3 AND low C4 (4 points)

Elevated anti-dsDNA, anti-Smith, or antiphospholipid antibodies, low complement (C3, C4, CH 50), or direct Coombs test (in the absence of hemolytic anemia)

Clinical Criteria
Constitutional Fever (2 points)

(temperature of more than 38.3 C or 100.94 F)

Hematologic

Hemolytic anemia (4 points)

Leukopenia (< 4,000 cells per mm3) (3 points)

Thrombocytopenia (platelet count < 100,000 cells per mm3) (4 points)

Hemolytic anemia

Leukopenia (< 4,000 cells per mm3) more than once or lymphopenia (< 1,000 cells per mm3) more than once or thrombocytopenia (platelet count < 100,000 cells per mm3)

Neuropsychiatric

1. Delirium (2 points):

Characterized by (1) change in consciousness or level of arousal with reduced ability to focus; (2) symptom development over hours to < 2 days; (3) symptom fluctuation throughout the day; (4) either (4a) acute/subacute change in cognition (e.g., memory deficit or disorientation), or (4b) change in behavior, mood, or affect (e.g., restlessness, reversal of sleep/wake cycle)

Seizures, psychosis, mononeuritis complex, myelitis, or peripheral or cranial neuropathy

Suggested Citation:"3 Systemic Lupus Erythematosus." 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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SYSTEM 2019 EULAR/ACR CRITERIA SLICC CRITERIA
Neuropsychiatric

2. Psychosis (3 Points):

Characterized by (1) delusions and/or hallucinations without insight and (2) absence of delirium;

3. Seizure (5 points):

Primary generalized seizure or partial/focal seizure

Mucocutaneous

Nonscarring alopecia (2 points);

Oral ulcers (2 points);

Subacute cutaneous or discoid lupus (4 points);

Acute cutaneous lupus (6 points)

Nonscarring alopecia

Oral or nasal ulcers

Acute cutaneous lupus or subacute cutaneous lupus

Chronic cutaneous lupus

Serosal

Pleuritis (5 points)

Pericarditis (6 points)

Imaging evidence (such as ultrasound, x-ray, CT scan, MRI) of pleural or pericardial effusion, or both

Serositis (pleurisy for more than 1 day, pleural effusion, or pleural rub; pericardial pain more than 1 day, pericardial effusion, pericardial rub, or pericarditis)

Musculoskeletal

Joint involvement (6 points)

Either (1) synovitis involving 2 or more joints characterized by swelling or effusion, or (2) tenderness in 2 or more joints and at least 30 minutes of morning stiffness

Synovitis involving 2 or more joints, or tenderness at 2 or more joints and at least 30 minutes of stiffness in the morning

Renal

Proteinuria > 0.5g/24h (4 points)

Renal biopsy Class II or V lupus nephritis (8 points)

Renal biopsy Class III or IV lupus nephritis (10 points)

Urinary creatinine (or 24-hour urinary protein) > 500 mg, or red blood cell casts

NOTE: For the ACR/EULAR criteria, classify as systemic lupus erythematosus with a score of 10 or more if entry criterion are fulfilled.

SOURCE: Aringer, 2019.

a positive ANA in addition to a score of 10 or greater across weighted criteria in 10 different domains (Hanly, 2004).

See Table 3-2 summarizing the updated immunologic classification criteria for SLE.

Suggested Citation:"3 Systemic Lupus Erythematosus." 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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Disease Course, Outcomes, and Variability

The disease course in SLE is variable, both between patients and within the same patient, and this contributes to the unpredictable nature of SLE outcomes. Still, SLE tends to follow one of three distinct patterns of disease activity: intermittent flares (relapsing–remitting), chronically active disease, and quiescent disease, with the relapsing–remitting course being most common (Steiman et al., 2014; Tselios et al., 2019). More than half of patients with SLE will have a disease flare after achieving a state of low disease activity or quiescence. Most of these flares are mild to moderate in severity and may involve one or more organ systems, most frequently the mucocutaneous, musculoskeletal, renal, hematological, or immunological systems. Almost one-third of flares, however, are clinically severe, with significant associated morbidity. Most severe flares may follow a moderate flare in the same organ system, and about one in five severe flares will manifest with new organ involvement or worsening of major organ disease (Adamichou and Bertsias, 2017).

Overall, the course of SLE disease will vary based on several factors, including ethnicity, gender, baseline disease activity and severity, immunological status, and the type of therapy received. Patient factors that confer an increased risk for disease flares include African descent, age of onset < 25 years, and male gender. Prior major organ disease (particularly renal and neuropsychiatric involvement), chronic disease activity, cytopenia, and withdrawal of immunosuppressant therapy are also associated with a high risk of disease flares. Consequently, affected patients may experience increased rates of end organ damage, with higher morbidity and mortality. In lupus nephritis particularly, frequent flares of renal disease are predictive of progression to chronic kidney disease (Parikh et al., 2014).

SLE disease activity is a measure of the underlying inflammatory process, which is generally reversible but can result in irreversible damage without timely therapy. Clinical severity in lupus can be considered mild, moderate, or severe, depending on specific organ involvement and the extent of organ involvement. For example, lupus disease activity involving the brain (lupus cerebritis) would be considered more severe and have greater consequences than disease activity manifesting as a localized skin rash. In general, active neuropsychiatric or renal involvement may denote a more severe course and increased mortality. Cardiopulmonary, gastrointestinal, and hematologic involvement may also be indicative of severe disease (Rosner et al., 1982).

Clinical assessment is critical in evaluating disease activity and is dependent on patient symptoms and examination findings of a new or ongoing inflammatory process. Diagnostic tests are used to confirm lupus activity; specifically, there may be elevated levels of inflammatory markers such

Suggested Citation:"3 Systemic Lupus Erythematosus." 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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as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), low levels of complement, and an increase in the double-stranded DNA (dsDNA) antibody. Additional tests specific to presenting symptoms and signs may confirm injury of the affected organ.

There are several validated scoring indices for monitoring disease activity and severity in SLE. These indices are generally used in clinical research trials and are not used in routine clinical practice as they are time consuming to complete. These indices include the Systemic Lupus Erythematosus Disease Activity Index-2K (SLEDAI-2K) and the Revised Systemic Lupus Activity Measure (SLAM-R), which estimate global SLE disease activity. Clinical manifestations are scored across several different organ systems, and a higher score indicates higher disease activity in the preceding 30 days (for SLEDAI-2K) or month (for SLAM-R). The British Isles Lupus Assessment Group-2004 (BILAG-2004) index measures disease activity in a single organ but can also provide a composite score for global disease activity. Additionally, there are indices developed by combining other scoring systems which are used exclusively in clinical trials such as the Systemic Lupus Erythematosus Response Index and the BILAG-Based Combined Lupus Assessment (Romero-Diaz et al., 2011).

SLE has a highly variable prognosis. Despite significant improvement in the overall prognosis of SLE in the last five decades, attributable to earlier diagnosis and treatment, the ability to detect milder disease, and therapeutic advances, patients with SLE have a mortality rate that is two to five times higher than the general population. SLE waxes and wanes throughout life, and features of the disease are highly variable from patient to patient. SLE remains a leading cause of death for young women, especially those of African and Hispanic ethnicity or those living in the Southern census region of the United States (Singh and Yen, 2018).

Early in the disease course, the main causes of death are active SLE (neurological and renal involvement) or infectious complications from immunosuppressant therapy. In late disease, death is related to damage accrual and complications due to SLE (chronic kidney disease), medication complications, and cardiovascular disease (Abu-Shakra et al., 1995; Yurkovich et al., 2014). Living with SLE is associated with significant morbidity, attributed to both the disease (active SLE and complications from SLE) and medication effects. Achieving true clinical remission in SLE (no clinical or serological disease activity) is rare, and patients often have relapses of disease activity (Medina-Quiñones et al., 2016), which means that SLE requires lifelong monitoring and clinical care.

Suggested Citation:"3 Systemic Lupus Erythematosus." 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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TREATMENT AND MANAGEMENT

The treatment and management of SLE, which is dependent on the organs and organ systems involved (see Table 3-3), ranges from prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) and antimalarials to intensive treatment with cytotoxic drugs or corticosteroids, or both. Additionally, patient education, physical and lifestyle measures and emotional support play a role in SLE management. In particular, learning stress reduction techniques, encouraging good sleep hygiene, exercise, and taking advantage of emotional support in addition to smoking cessation, certain dietary restriction (e.g., avoiding alfalfa sprouts and echinacea), and avoiding direct sunlight might all be helpful (Vaillant et al., 2022).

The goals of treatment are to prevent organ damage and, if possible, to achieve remission. Table 3-3 describes the types of medication used to treat specific manifestations of the disease.

Antimalarials are still considered to be important in the treatment of SLE. Hydroxychloroquine, an antimalarial drug, is critical in the treatment of SLE as it manages the active manifestations of the disease, including anti-thrombotic properties and preventing flares, but its use does not indicate the severity of disease as it is prescribed as baseline therapy for all patients with SLE. Patients on monotherapy with hydroxychloroquine are likely to have mild stable disease, but the risk for SLE flares with serious consequences (though decreased) still persists. Patients on hydroxychloroquine will require regular ophthalmology exams to monitor for retinopathy associated with the drug. Glucocorticosteroids are also frequently used in SLE management; however, there are numerous long-term effects including osteoporosis, glaucoma, cataract, and avascular necrosis. Further, patients on high-dose corticosteroids will need antibiotic prophylaxis to prevent certain opportunistic infections. Immunosuppressive agents used in SLE treatment have potential adverse effects ranging from

TABLE 3-3 Management and Treatment of Systemic Lupus Erythematosus

Manifestation Treatment/management
Cutaneous Mild cutaneous manifestations: topical corticosteroids or topical calcineurin inhibitors (e.g., tacrolimus), hydroxychloroquine or quinacrine are very efficacious; methotrexate if no response to hydroxychloroquine. For severe or resistant disease, systemic corticosteroids, mycophenolate mofetil, belimumab or anifrolumab, can be considered. Other medications include thalidomide, cyclophosphamide, IVIG, and rituximab for more severe manifestations.
Suggested Citation:"3 Systemic Lupus Erythematosus." 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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Manifestation Treatment/management
Musculoskeletal Hydroxychloroquine is the initial drug of choice; if no response, methotrexate or leflunomide can be used. Belimumab, anifrolumab, and rituximab can be used in refractory cases.
Hematologic Mild cytopenias usually do not require treatment. For moderate to severe cytopenias, corticosteroids are used. Alternatives to steroids are azathioprine or cyclosporine-A. Severe cases might require IV pulse-dose steroids, mycophenolate mofetil, rituximab, cyclophosphamide, plasmapheresis, recombinant G-CSF, or splenectomy.
Cardiopulmonary NSAIDs or corticosteroids may be used for serositis, while hydroxychloroquine, azathioprine, or methotrexate can be used as steroid-sparing agents.
Acute lupus pneumonitis requires high-dose IV pulse corticosteroids with plasmapheresis and/or cyclophosphamide if diffuse alveolar hemorrhage present.
Interstitial lung disease is treated with low- to moderate-dose corticosteroids with immunosuppressive agents such as azathioprine or mycophenolate mofetil.
Pulmonary arterial hypertension requires vasodilator therapy, while thrombotic complications such as pulmonary embolism require anticoagulation.
High-dose corticosteroids are required for the management of myocarditis and coronary arteritis.
Central nervous system High-dose corticosteroids with immunosuppressive agents such as cyclophosphamide, azathioprine, or rituximab are used for inflammation-related neuropsychiatric manifestations such as optic neuritis, aseptic meningitis, demyelinating disease, etc.
Lifelong warfarin is indicated in cases of thromboembolic CNS events associated with antiphospholipid antibody syndrome.
High-dose corticosteroids can be used in cognitive impairment.
Renal Class I and II lupus nephritis (LN) (confirmed with biopsy) can be treated with the renin-angiotensin-aldosterone system blockade, as can mild membranous LN (Class V).
Class III–IV and moderate to severe Class V LN can be treated with immunosuppression with corticosteroids followed by mycophenolate mofetil/IV cyclophosphamide followed by maintenance therapy with mycophenolate mofetil or azathioprine +/- belimumab or voclosporin.

NOTE: CNS = central nervous system; G-CSF = granulocyte colony stimulating factor; IV = intravenous; IVIG = intravenous immunoglobulin; LN = lupus nephritis; NSAID = nonsteroidal anti-inflammatory drug.

SOURCE: Table developed from Vaillant et al., 2022.

Suggested Citation:"3 Systemic Lupus Erythematosus." 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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cytopenias and hepatotoxicity to an increased risk of urinary bladder cancer with cyclophosphamide. SLE patients on those medications should be closely monitored for adverse effects (Vaillant et al., 2022). It should be noted that belimumab, a monoclonal antibody that inhibits B-lymphocyte stimulator, was the first targeted biologic agent approved for the treatment of SLE. Anifrolumab, a type I interferon receptor antagonist, was recently approved for the treatment of patients with moderate to severe SLE who fail to respond to standard therapy. Both therapies have been shown to allow for reductions in cumulative glucocorticoid exposure (Basta et al., 2020). Combination therapy and the use of corticosteroids or biologic or cytotoxic therapy indicate more severe SLE.

Table 3-3 (above) highlights the specific manifestations of SLE organized by the organ or system involved along with the drugs used to treat those manifestation, whereas Table 3-4 focuses on the type of medications and their side effects.

Overall, the goals of treatment are to maintain the lowest degree of disease activity (using immunomodulators and immunosuppression) in an effort to prevent organ damage and to reduce comorbidities secondary to lupus and its treatment, and to address fatigue and pain (Fava and Petri, 2019).

Clinical Practice Guidelines for Receiving Treatments

All established treatment guidelines for the treatment and management of SLE agree that the aim of treatment is to induce and maintain low disease activity, prevent disease flares, and reduce comorbidities while safeguarding against the toxic effects of the immunosuppressant therapies (Fanouriakis et al., 2019). The 2019 update of the EULAR recommendations for the management of SLE indicates that patients with SLE should ideally be managed by a rheumatologist, with shared decision making around therapeutic regimens and goals. Given the heterogenous and variable nature of the disease, treatment regimens should be individualized; however, some general rules apply to all patients with SLE. Antimalarial therapy with hydroxychloroquine or chloroquine should be a component of all treatment strategies unless there is a contraindication to use. Antimalarials are effective in relieving constitutional symptoms as well as mucocutaneous and musculoskeletal manifestations, and they may reduce disease flares, damage accrual, and mortality. Additional therapy is dependent on the disease severity and manifestations. Immunosuppressant therapy can relieve inflammation and induce clinical quiescence; however, some patients may have refractory disease, and SLE flares may occur with withdrawal of therapy. Early treatment can prevent damage accrual and hence reduce comorbidities, but the opportunity for it is hindered by the fact that many patients with SLE have a delayed diagnosis.

Suggested Citation:"3 Systemic Lupus Erythematosus." 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 3-4 Medications for the Management and Treatment of SLE and Potential Side Effects

Treatment/medication type Medication Potential side effects
Immunomodulators *Hydroxychloroquine Retinopathy, increased after 20 years of continuous use. Cardiac and neuromyopathic toxicities are very rare.
Vitamin D Serum levels higher than 150 ng/mL are associated with vitamin D intoxication (e.g., hypercalcemia, hypercalciuria, and calcifications).
Dehydroeipandrosterone (DHEA) Weak androgen with modest immune modulatory effects in women. May increase risk of hormone sensitive malignancies and should be avoided in postmenopausal women.
Corticosteroids Adrenocorticotrophic hormone (ACTH)—increases the production of adrenal steroids and other hormones, including cortisol, prednisone, methyprednisone, and triamcinolone Suppressed immune system, increased risk of infections, high blood pressure, central obesity, osteoporosis, depression, high blood sugar, glaucoma, and cataracts.
Cytotoxic immunosuppressants Azathoprine
Methotrexate
Mycophenolate
Cyclophosphamide
Calcineurin inhibitors (e.g., cyclosporine, tacrolimus, and *voclosporin)
Cytopenia, liver inflammation, nausea, vomiting, diarrhea, increased risk for infection, and malignancy.
Methotrexate, mycophenolate, and cyclophosphamide are teratogenic agents.
Biologics and small molecules *Belimumab
*Anifrolumab
Increased risk for infection, infusion reactions, gastrointestinal intolerance.

NOTE: * = therapies that are approved for the treatment of SLE or lupus nephritis by the U.S. Food and Drug Administration.

SOURCE: Table adapted and summarized from Fava and Petri, 2019.

Suggested Citation:"3 Systemic Lupus Erythematosus." 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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Specific guidelines have also been published for the treatment and management of lupus nephritis, a common complication of SLE with an associated high morbidity and mortality. The 2019 update of the joint EULAR and European Renal Association–European Dialysis and Transplant Association (ERA–EDTA) recommendations for the management of lupus nephritis reflect the most recent scientific data. The guidelines reiterate the importance of regular screening for renal involvement and the role of kidney biopsy in the presence of persistent proteinuria ≥ 0.5g/24hours (or urine protein–creatine ratio ≥ 500mg/g in morning first void urine) or an unexplained change in renal function. Immunosuppressive agents (mycophenolate or cychlophosphamide) in combination with glucocorticoids are recommended when class III and class IV lupus nephritis occurs or when pure class V nephritis occurs in the presence of nephrotic-range proteinuria despite therapy with renin–angiotensin–aldosterone system blockers. These recommendations endorse the concomitant use of hydroxychloroquine and prioritize rapid tapering of glucocorticoid therapy over 3–6 months as the disease response allows. Once the disease is quiescent, patients will require maintenance immunosuppressive therapy, and attempts to decrease the therapy should only be made after 3–5 years of complete remission of kidney disease. Treatment of SLE and lupus nephritis is a rapidly evolving area with several novel therapeutic agents in clinical trials (see Table 3-5). Only one U.S. Food and Drug Administration (FDA)-approved therapy for SLE was available when the 2019 EULAR/ERA-EDTA recommendations were published.

There are currently three FDA-approved therapies for SLE and three therapies approved specifically for lupus nephritis (see Table 3-4). In general, traditional therapies (Table 3-3), which have longstanding efficacy and safety data for other autoimmune conditions, have complemented the treatment strategy for moderate to severe SLE. Newer therapies (e.g., small molecules, biologics) are being studied to establish efficacy in lupus, as are several novel investigational products (see Tables 3-4 and 3-5).

Antimalarials, belimumab, anifrolumab, and steroids are FDA-approved drugs for the treatment of SLE, and voclosporin is FDA approved specifically for lupus nephritis. FDA approved the first drug to treat lupus, asprin, in 1948 and later approved corticosteroids, such as prednisone (which suppresses the immune system and reduces inflammation). In 1955 the antimalarial drug Plaquenil (hydroxychloroquine) was approved to relieve some symptoms of lupus such as fatigue, rashes, joint pain, and mouth sores. Belimumab (Benlysta), which was specifically designed for the treatment of lupus, was recently approved by FDA. It targets specific immune cells, rather than taking the more general approach of other therapies that suppress the entire immune system. Saphnelo (anifrolumab-fnia) also has been

Suggested Citation:"3 Systemic Lupus Erythematosus." 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 3-5 Novel Therapeutic Agents for Systemic Lupus Erythematosus Currently in Phase 2 or 3 Clinical Trials

Drug Mechanism of Action Sponsor
Obinutuzumab Anti-CD20 monoclonal antibody Hoffman-La Roche/Genentech
Dapirolizumab pegol Polyethylene glycol-conjugated Fab’ fragment, which targets CD40 ligand Union Chimique Belge (UCB)
SAR441344 Anti-CD40 monoclonal Ab Sanofi
Iscalimab Anti-CD40 monoclonal Ab Novartis
Ianalumab Anti-BAFF (B-cell activating factor) IgG1 antibody Novartis
AMG 570 Inhibition of the co-stimulator ligand (ICOSL) and B-cell activating factor (BAFF) Amgen
Upadacitinib JAK1 selective inhibitor AbbVie
Baracitinib JAK1 and JAK2 inhibitor Eli Lilly
Brepocitinib JAK1 and TYK2 inhibitor Pfizer
Deucravacitinib TYK 2 inhibitor Bristol Myers Squibb
Tofacitinib JAK inhibitor Pfizer
Orelabrutinib Tyrosine kinase inhibitor Beijing InnoCare Pharma Tech Co., Ltd.
Branebrutinib Bruton’s tyrosine kinase (BTK) Bristol Myers Squibb
Acazicolcept Inhibitor of the CD28 and ICOS T-cell costimulatory pathways Alpine Immune Science
Efavaleukin alfa IL-2 mutein Fc fusion protein—expands Tregs (regulatory T-cells) Amgen
Secukinumab IL-17A inhibitor Novartis
LY3471851 IL-2 receptor antagonist Eli Lily
Nipocalimab IgG1 anti-FcRn monoclonal antibody Janssenn
BIIB059 Monoclonal antibody that binds blood dendritic cell antigen 2 (BDCA2) Biogen Inc.
VIB7734 Monoclonal antibody that targets plasmacytoid dendritic cells (pDC) Viela Bio inc.
KZR-616 Selective inhibitor of the immunoproteasome Kezar Life Sciences, Inc.
Afimetoran Toll-like receptor 7/8 Antagonist Bristol Myers Squibb
Cenerimod Sphingosine 1-phosphate 1 receptor modulator Idorsia
Iberdomide High-affinity cereblon ligand Celgene
Suggested Citation:"3 Systemic Lupus Erythematosus." 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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recently approved in the United States for the treatment of adult patients with moderate to severe SLE who are receiving standard therapy.

Currently several medications in use for lupus have been borrowed from other diseases and conditions and are used off-label as they are not approved by the FDA specifically for lupus. These drugs include anti-cancer drugs (azathioprine, methotrexate, cyclophosphamide), organ-rejection drugs (mycophenolate mofetil), and biologic agents (rituximab, abatacept). Developing drugs to treat SLE is an active area of research, and several molecules are being investigated.

Likelihood of Improvement Given Treatment

Despite advancements in therapeutic options and a better understanding of the disease, SLE patients suffer from high morbidity and mortality. Survival rates are 85 to 90 percent during the first 10 years. Complications may arise from organ damage due to the disease or from the adverse effects of the medications, such as infection and fatigue (see Chapter 2 for common side effects of treatment). Both the medications and their potential adverse effects can affect function.

Secondary Impairments from Treatment

Medication-induced complications are common. Long-term corticosteroid use in SLE patients frequently leads to osteoporosis and undertreated osteoporotic fractures. Additional complications from corticosteroid use include opportunistic infections, hyperglycemia, hypertension, and acute psychosis. Further, corticosteroid therapy is associated with avascular necrosis, glaucoma, cataract, weight gain, and poor control of diabetes mellitus.

Long-term use of hydroxychloroquine may result in irreversible maculopathy and retinopathy. Cyclophosphamide use is associated with a high risk of interstitial cystitis and bladder cancer, even after its use has been discontinued. SLE patients are immunocompromised and are at a significantly greater risk of infections, resulting in morbidity and mortality (Vaillant et al., 2022).

Select Treatments Currently in Clinical Trials

A challenge in treating patients with SLE is the paucity of approved therapeutics for treating the many diverse manifestations of the disease. Barriers to drug development include the heterogeneity of the disease, trials of inadequate size or duration, insufficient dose finding before trial initiation, issues related to the management of background medications, and questions about the choice of the primary endpoint (Mahieu et al., 2016).

Suggested Citation:"3 Systemic Lupus Erythematosus." 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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There are many clinical trials in progress for therapeutic interventions for SLE. A search on the National Institutes of Health (NIH) National Library of Medicine website currently lists 358 studies in adults for SLE in the United States (NIH, 2021).

When the committee searched using the following criteria—all active, phase 2 or 3 studies for SLE, all ages—a list of 57 studies was returned. Table 3-5 lists 25 of the novel therapeutic agents currently in phase 2 and 3 clinical trials in the United States. The trials include studies targeting B-cells, plasma cells, co-stimulation, cytokines and their receptors, complement factors or interferons, and the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Although clinical trials are under way to study potential therapies, several targeted therapies have not performed as expected in large phase 3 trials. Many of the current B-cell targeted therapies which should theoretically be effective have not yielded success in treating SLE. Despite this, efforts are ongoing to demonstrate efficacy with obinutuzumab, a potent anti-CD20 agent that has B-cell depletion superior to rituximab, with promising preliminary results from phase 3 clinical trials. A description of all of the agents under investigation in SLE is beyond the scope of this work, but clinical research in SLE therapeutics remains an area of active and avid interest in hopes of a major breakthrough in the management of this complex disorder (Bag-Ozbek and Hui-Yuen, 2021).

DISEASE-SPECIFIC FUNCTIONAL LIMITATIONS

People with SLE often have functional impairments that lead to difficulties in physical functioning. In a study looking at a wide range of “valued life activities (VLAs),” ranging from self-care to household chores, social activities, and recreation, almost half of a large cohort of people with SLE were unable to perform one or more VLAs, and 25 percent experienced an increase in the number of activities they were unable to perform over a 1-year period (Katz et al., 2008). Disease activity accounted for the majority of activity impairment. The impact of SLE on physical functioning depends largely on the severity of the disease activity and on which disease manifestations are present, with severe fatigue, neurocognitive symptoms, and musculoskeletal symptoms often associated with the greatest difficulties (Drenkard et al., 2014; Yelin et al., 2009, 2012). Factors not generally recognized as manifestations of lupus but which have more recently been shown to be associated with poor physical functioning and functional decline are muscle weakness, which is associated with systemic inflammation, and frailty, a constellation of symptoms reflecting general susceptibility to physical stressors (Andrews et al., 2015; Katz et al., 2017).

Suggested Citation:"3 Systemic Lupus Erythematosus." 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 impact of SLE on workforce participation is well documented (Booth et al., 2018; Drenkard et al., 2014; Yelin et al., 2007, 2012). Studies have consistently shown higher levels of work disability, absenteeism, and health-related retirement or withdrawal from employment. As an example, among a large population-based cohort of people with lupus, 49 percent experienced work loss within an average disease duration of 13 years (Drenkard et al., 2014). Overall, the standardized unemployment ratio (SUR) was 3.61 (95 percent confidence interval 3.24–4.03). Those with severe disease activity and severe organ damage had the highest risks of unemployment (4.38 [3.82–5.01] and 5.56 [4.57–6.76], respectively). Among those who remained employed, severe fatigue, neurocognitive symptoms, and musculoskeletal symptoms had the greatest impact on work productivity. Other studies have shown that the risk of work loss is increased by lower cognitive and physical functioning, higher levels of depressive symptoms, and specific SLE manifestations such as thrombosis and musculoskeletal problems (Panopalis et al., 2008; Yelin et al., 2009, 2012). Data from the UCSF Lupus Outcomes Study, a longitudinal cohort of 1,204 persons with SLE sampled between 2002 and 2009, found that by 4 years follow-up, 57 percent, 34 percent, and 38 percent of those with thrombotic, musculoskeletal, and neuropsychiatric manifestations, respectively, had stopped working, as had 42 percent of those with increased disease activity. On a bivariable basis, the risk of work loss was significantly higher among persons aged 55–64 years, and in those with increased disease activity and with each type of clinical manifestation (as noted above) (Yelin et al., 2012). Disease fluctuations or flares may also increase absenteeism and affect an individual’s ability to maintain employment (Booth et al., 2018; Katz et al., 2020).

Children with SLE have poorer school performance and meet fewer educational milestones (Groot et al., 2021; Zelko et al., 2012), which can affect long-term employment. Adults with childhood-onset SLE are less likely to be employed that those with adult-onset SLE, despite having similar education levels, and vocational choices may be affected by childhood-onset SLE (Lawson et al., 2014) The characteristics of work also influence work loss or retention (Booth et al., 2018; Yelin et al., 2007). High physical and psychological demands of a job and little control over the pace or timing of work or work tasks are associated with greater work loss. Reductions in hours or changes in job content may improve the chances of remaining employed.

CHILDHOOD-ONSET SLE

Childhood-onset SLE (cSLE) is rare and characterized by significant morbidity and mortality with widespread organ involvement, including

Suggested Citation:"3 Systemic Lupus Erythematosus." 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 kidneys and brain. Tests for SLE in early stages lack specificity, and a diagnosis is often made after organ damage is manifest. Disease patterns are highly variable; flares are not predictable and not always associated with biomarkers (Thong and Olsen, 2017). cSLE has a distinct pattern of organ involvement (see below) and is characterized by autoantibody formation. About 10–20 percent of all patients with SLE are diagnosed during childhood.

cSLE has a reported annual incidence of 0.3–0.9 per 100,000 children and a prevalence of 3.3–24 per 100,000 children (Harry et al., 2018). Typically, cSLE exhibits a more severe course than what is seen in adults. Children most often develop SLE in their teen years, with 12 years of age as the average age of onset; it is rarely seen before the age of 5. As with adult-onset SLE, there is a higher frequency in African Americans, Asians, Hispanics, and Native Americans than in whites.

The symptoms that children experience are very similar to those seen in adults, but they may be more severe and involve more organs. Patients diagnosed with cSLE frequently report nonspecific symptoms including fever, fatigue, anorexia, weight loss, alopecia, and arthralgias. Those and other symptoms of diffuse generalized inflammation (including lymphadenopathy and hepatosplenomegaly) can occur at onset and during disease flares (Levy and Kamphuis, 2012).

Specifically, the clinical features in children may include

  • A red rash on the cheeks and bridge of the nose;
  • A disc-shaped rash (discoid lupus) with raised patches;
  • Arthritis in two or more joints (often fingers and toes);
  • Fluid build-up surrounding the heart or lungs;
  • Kidney problems;
  • Seizures; and
  • Low red blood cell, platelet, or white blood cell counts.

Children with SLE will have abnormal antibody results and high readings for ANAs. However, ANAs are not specific to cSLE and can occur in other rheumatologic diseases, such as juvenile idiopathic arthritis and juvenile dermatomyositis. Malignancies and infections can result in transient ANA positivity. Anti-double-stranded DNA positivity is very specific for SLE and present in up to 75 percent of patients with cSLE (Harry et al., 2018).

The focus of treatment of cSLE is on controlling symptoms and managing symptoms over time. Treatment goals include the control of cSLE activity, flare avoidance, damage prevention, and minimizing the effects of medication. The medical specialists who treat cSLE can include a pediatric rheumatologist, nurses, counselors, physical therapists, and others.

Suggested Citation:"3 Systemic Lupus Erythematosus." 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 impairment may be seen in as many as 59 percent of children and adolescents with SLE, and available data do not suggest that demographic factors such as race and ethnicity are predictive of cognitive impairment. While no consistent pattern of cognitive impairment has been observed, and the degree of impairment can range from mild to severe dementia, abnormalities in processing speed, verbal memory, working memory, visuospatial learning, and attention have been reported (Levy et al., 2009). Diagnosing cognitive impairment in pediatric SLE patients is challenging and has not been extensively studied. A wide range of instruments are available for neurocognitive testing, but no standardized battery has been validated for the pediatric SLE population.

Similar to treating adults with SLE, medications for children with SLE can include

  • Corticosteroids (prednisone) to control inflammation;
  • Hydroxychloroquine, an anti-malarial drug used to control disease flares;
  • Immunosuppressants: azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab, and belimumab;
  • Pain relievers such as ibuprofen and naproxen; and
  • Calcium and vitamin D supplements.

Higher prednisone doses predict a higher damage trajectory, and antimalarial exposure is found to be protective. Long-term studies of adults with cSLE confirm that damage accrual increases with disease duration. Cardiovascular disease, renal transplants, replacement arthroplasties, and myocardial infarctions occur between 20 and 40 years of age (Rodriguez-Smith and Brunner, 2019).

As noted earlier, children with SLE do not achieve long-lasting, drug-free remission, and many patients require long-term immunosuppressive treatment. Mortality rates, however, have decreased, with 10- and 15-year survival rates exceeding 85 percent. With longer survival there has been an increase in long-term comorbidities, including premature atherosclerosis, myocardial infarction, ESRD requiring dialysis or renal transplant with concomitant morbidities, osteoporosis (leading to bone fragility and fracture risk, joint replacement), multiple hospitalizations due to infection and other treatment-related complications, and an increased risk of malignancy (Levy and Kamphuis, 2012). More than a third of cSLE patients report that the disease has negatively affected their education, and most adults with cSLE live on low incomes, and a small percent (11–23 percent) live on full-time disability support. Assessments of health-related quality of life demonstrate significantly lower scores for cSLE patients than in healthy controls (Levy and Kamphuis, 2012).

Suggested Citation:"3 Systemic Lupus Erythematosus." 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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SUMMARY

SLE is a potentially fatal autoimmune disease. It is a chronic, multisystem disease with several phenotypes and is characterized by inflammation of different tissues of the body. The clinical features may vary from mild disease to severe, life-threatening disease with multi-organ involvement. People with SLE often have functional impairments that lead to difficulties in physical functioning. The impact of SLE on physical functioning depends largely on the severity of the disease activity and on which disease manifestations are present, with severe fatigue, neurocognitive symptoms, and musculoskeletal symptoms often associated with the greatest difficulties. The disease disproportionately affects women and minorities; African Americans with SLE have more severe disease and develop it at an earlier age. It is often difficult to diagnose because many of the symptoms are nonspecific and overlap with other common diseases. The causes of SLE are unknown but are believed to be linked to genetic, environmental, and hormonal factors. Women of childbearing ages are at greatest risk of developing SLE.

In people diagnosed with SLE, the immune system attacks the body and creates inflammation in the skin, joints, kidneys, lungs, nervous system, and other organs of the body. There can be times of active disease, called a flare, and times where the disease is mostly quiet, called remission. About 20 percent of people with lupus develop the disease before 20 years of age. It is rare to get lupus before 5 years of age. Lupus is more common in females and in certain ethnic groups, including African American, Hispanic, South and Southeast Asian, and American Indian/Alaska Native populations, which tend to have a more severe clinical phenotype.

Diagnosing SLE can be challenging, and treatment depends on the organ systems involved. Despite advancements in SLE treatment and a better understanding of the disease, SLE patients have significant morbidity and mortality. Survival rates are 85 to 90 percent during the first 10 years; the leading causes of mortality include cardiovascular disease, infections, and renal disease.

With regard to the treatment of SLE patients, traditional therapies have included hydroxychloroquine, systemic glucocorticosteroids, and conventional immunosuppressive drugs and biologic agents (e.g., belimumab), and more novel therapies, for example, targeting interferons, cytokines and their receptors, intracellular signals, plasma cells, and T-lymphocytes. A diagnosis of SLE during childhood is an important risk factor for morbidity and mortality. The increased risk is attributed to organ damage and the adverse effects of medication, particularly long-term steroid use. Childhood SLE has negative affects on growth and development and interferes with social and cognitive skills.

Suggested Citation:"3 Systemic Lupus Erythematosus." 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:"3 Systemic Lupus Erythematosus." 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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