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Selected Immune Disorders and Disability (2022)

Chapter: 4 Scleroderma

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Suggested Citation:"4 Scleroderma." 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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4

Scleroderma

Systemic sclerosis (SSc), or scleroderma, is a chronic, multisystem autoimmune rheumatic disease characterized by exaggerated fibrosis, vasculopathy, and derangements of the immune system. When scleroderma only affects the skin, it is considered “localized” and referred to as scleroderma, however, if it affects the skin and internal organs, it is considered “systemic,” and referred to as systemic sclerosis (SSc). SSc affects approximately 100,000 people, or about one-third of patients with scleroderma in the United States. The hallmark of SSc is its clinical heterogeneity, as the disease encompasses several distinct sub-phenotypes and autoantibody groups with a disease course, risk of complications, and response to therapy that are all highly variable. Medical providers must carefully characterize each patient to understand the specific manifestations, level of disease activity, and risk for organ specific complications, as this influences potential screening and therapeutic strategies (Shah and Wigley, 2013).

The etiopathogenesis of SSc is likely complex with multiple potential contributing factors, including genetic predisposition, environmental or chemical exposures, malignancy or its treatment with chemotherapy, immunotherapy or radiation, and other factors. SSc is rare, with an estimated 1 in 10,000 individuals having the disease (Denton and Khanna, 2017). Females are 4.6 times more likely than males to be affected (Mayes et al., 2003), and the disease is rare in children. The peak age of SSc onset is 45–60 years, and older individuals developing new-onset SSc tend to have a worse prognosis (Shah and Wigley, 2013). The disease also tends to be more severe in African Americans and Native Americans than in white Americans (Arnett et al., 1996; Otero et al., 2017; Steen et al., 2012). Although

Suggested Citation:"4 Scleroderma." 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 disease is rare in men, when present it has a more severe expression, including more internal organ–based complications and higher mortality than in women (Hughes et al., 2020). Despite improvements in survival over time, SSc has the highest mortality of all rheumatic diseases (Denton and Khanna, 2017).

This chapter covers the clinical features, diagnosis, and disease course; treatment and management; and disease-specific limitations of scleroderma and systemic sclerosis, including how the disease affects children.

CLINICAL FEATURES, DIAGNOSIS, AND DISEASE COURSE

Clinical Features

This section will discuss the clinical features, or presentation, of scleroderma and systemic sclerosis. There are two primary forms of scleroderma: localized and systemic, the latter of which is often called systemic sclerosis. Localized scleroderma is confined to the skin and underlying tissue. Its outcome is unpredictable, and spontaneous improvements are possible. Different forms of localized scleroderma can coexist in the same patient. The two main groups of localized scleroderma are morphea and linear scleroderma (Odonwodo et al., 2020).

SSc is usually more severe than localized scleroderma because it affects multiple internal organs. In SSc the classic clinical presentation is in a young or middle-aged woman with Raynaud’s phenomenon (discussed below) and skin changes accompanied by musculoskeletal discomfort and gastrointestinal (GI) symptoms. For patients with diffuse cutaneous systemic sclerosis (dcSSc) the skin disease often worsens in its first 12–18 months. The skin thickening may then stabilize and even soften over 3–5 years, but with considerable variation among patients. There are numerous complications that can occur, usually in the first 5 years, including interstitial lung disease (ILD), renal crisis, and myopathy; on the other hand, pulmonary hypertension occurs later in the disease. However, those various complications appear in approximately 15 percent of the patients.

Figure 4-1 contains images of clinical features of SSc and the following sections describe the specifics of its various clinical manifestations.

Raynaud’s Phenomenon and its Complications

Early detection of SSc may provide a window of opportunity to manage the disease before irreversible, end-organ damage occurs. Most commonly, the first sign of SSc is the development of Raynaud’s phenomenon, which occurs due to cold- or stress-induced vasospasm of digital arteries and

Suggested Citation:"4 Scleroderma." 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 4-1 Clinical features in systemic sclerosis.
NOTE: A, grossly detailed nailfold capillaries; B, ischemic digital ulcer; C, matted telangiectasia; D, sclerodactyly and hand scleroderma with finger flexion contractures; E, forearm scleroderma with papules due to fibrosis of dermis with lymph-edema; F, subcutaneous calcinosis.
SOURCE: Shaw and Wigley, 2013, with permission.

cutaneous arterioles, which play a critical role in thermoregulation (Shah and Wigley, 2013). Patients with primary Raynaud’s phenomenon have a younger age of onset (between 15 and 30 years) than those with secondary Raynaud’s phenomenon, and there is no evidence of a secondary cause (e.g., peripheral vascular disease, digital ischemic injury, or abnormal nailfold capillaries) (Wigley and Flavahan, 2016).

Suggested Citation:"4 Scleroderma." 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 addition to causing color changes (classically pallor, violaceous discoloration, and then erythema) of tissues such as the fingers, feet, ears, nose, and nipples, Raynaud’s can cause significant pain, numbness, and tingling affecting basic hand functioning. While Raynaud’s occurs commonly in the general population (approximately 3–5 percent), Raynaud’s phenomenon in SSc is often more severe, likely due to the vasculopathy of SSc. As a result, patients with SSc may develop ischemic digital ulcerations causing visible loss of epithelium and significant pain, with a risk for superimposed infection. Ischemic digital ulcers can take many weeks to resolve (at times more than 12 weeks); because many patients develop recurrent ulcerations with the involvement of multiple fingertips, this can result in chronic impairment of hand function with a reduced ability to perform fine motor functions. Fingertip pitting scars and acro-osteolysis may develop as a consequence of tissue ischemia. Patients may also develop critical digital ischemia, and this often causes substantial pain and can result in gangrene and tissue loss by autoamputation or surgical amputation.

Beyond the physical aspects, Raynaud’s phenomenon can have significant emotional impact on patients, causing distress, annoyance, and embarrassment (Pauling et al., 2018). Patients often require constant vigilance and self-management, and adaptive strategies, such as wearing gloves to perform basic activities, often makes it more challenging to complete their daily home and work-related tasks.

Skin/Cutaneous Manifestations

Skin thickening due to dermal fibrosis is a very common physical finding in SSc, although a small percentage of patients have no skin thickening, in which case the condition is referred to as systemic sclerosis sine scleroderma. Among those with skin thickening, there is significant variability in the pattern and extent of skin involvement. Patients are typically classified into two major cutaneous subsets based on the extent of skin sclerosis: limited (skin involvement limited to fingers, hands, forearms, lower legs, feet, and face) and diffuse (extending to proximal upper or lower extremities or trunk) (LeRoy et al., 1988). Diffuse and limited have different natural histories with increased mortality and morbidity in the diffuse SSc population. Diffuse cutaneous disease is seen in 30–40 percent of SSc patients in most international cohorts.

Patients may present with inflammatory skin changes, often with puffy or swollen fingers. This early edematous phase can extend beyond the fingers to involve the hands, feet, and more proximal tissues. This presentation may be confused with other clinical conditions, and patients may be prescribed diuretics or treated for carpal tunnel syndrome initially. There can be musculoskeletal pain suggestive of inflammatory joint disease, and patients may receive

Suggested Citation:"4 Scleroderma." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
×

a diagnosis of rheumatoid arthritis (RA) until the clinical picture evolves. In patients with more extensive limited skin involvement or diffuse skin disease, itching and neuropathic discomfort of the skin can be severe. Hyper- and hypo-pigmentation may develop, often with a salt-and-pepper appearance of the skin, which can be cosmetically and socially distressing. Patients in the early active phase of SSc may also have tendon friction rubs and develop joint contractures (see section on Musculoskeletal Disease below).

In patients with more extensive limited scleroderma or diffuse skin disease, the skin disease may worsen in the first 12–18 months, with progressive skin thickening and involvement of new body areas. This may be followed by a period of stabilization and later softening of the skin. At a population level, the time course of skin progression, stabilization, and softening is 3–5 years. For individual patients, however, the trajectory of skin involvement is highly variable in terms of the rapidity of progression, the peak extent of skin involvement, whether there is softening and to what extent, and the degree of disability that ensues. The extent and severity of skin disease is measured by clinicians using the modified Rodnan skin score (mRSS), which is derived from a physical examination. Clinicians score the extent of dermal fibrosis using a 0–3 scale1 (0 = no skin thickening, 1 = mild skin thickening, 2 = moderate skin thickening, 3 = severe skin thickening) in 17 different body areas (bilateral fingers, hands, forearms, upper arms, thighs, legs, feet, face, chest, abdomen) for a total possible score of 51. The mRSS is thought to be a good measure of disease severity, but it does not fully encompass the spectrum of disease activity. It may lag other measures of disease activity, such as patient-reported pruritis and cutaneous discomfort, skin thickening, and tendon friction rubs.

Over time, skin thickening may result in perioral furrowing and microstomia, and this may contribute to social distress, difficulty with eating, and challenges maintaining good oral hygiene. Other cutaneous manifestations include the development of telangiectasia, which is considered to be a marker of ongoing vascular injury and defective repair in SSc (Shah et al., 2010).

Gastrointestinal Manifestations

GI manifestations are common in SSc and may result in significant morbidity, a poor nutritional state, and an impaired quality of life. Facial skin thickening and microstomia can limit oral intake and the mechanics of mastication. Sicca symptoms similar to those observed in Sjögren’s syndrome may cause dry mouth, impaired bolus transfer and swallowing, dental decay, and loosening of teeth. Pharyngeal muscle weakness due

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1 A mRSS score of 0 is normal or no skin thickening.

Suggested Citation:"4 Scleroderma." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
×

to myositis or myopathy can contribute to globus sensation and oropharyngeal dysphagia. A common manifestation is gastroesophageal reflux disease due to esophageal dysmotility and a hypotensive lower esophageal sphincter. Patients may present with heartburn, chronic cough, or hoarse voice. Reflux can increase the risk of esophageal stricture, distal dysphagia, and development of Barrett’s esophagus and esophageal cancer. This may also increase the risk of aspiration pneumonia and contribute to the development or worsening of interstitial lung disease (see below) (Christmann et al., 2010). Early satiety may develop secondary to gastroparesis. Upper GI tract involvement can result in the regurgitation of food, further impairing nutrition. Gastric antral vascular ectasia (GAVE) or watermelon stomach may result in melena, acute and chronic GI blood loss, and anemia. Similar vascular lesions may less commonly develop in other regions of the GI tract and cause GI bleeding. Small intestine bacterial overgrowth may develop in the setting of lower GI tract dysmotility and contribute to nausea, vomiting, early satiety, abdominal distension, diarrhea, and weight loss (Marie et al., 2009). Delayed colonic transit may also result in abdominal distension, constipation, fecal impaction, and intestinal pseudo-obstruction, which can become chronic and contribute to malnutrition (McMahan et al., 2020). Anorectal dysfunction may cause distressing fecal incontinence which impairs a patient’s ability to function in social and work environments. All of the above factors and malabsorption can result in malnutrition and cachexia, which in severe cases may require total parenteral nutrition.

Musculoskeletal Disease

Musculoskeletal disease is commonly disabling in scleroderma, with significant impairments in the ability to perform activities of daily living. Most patients have skin thickening involving the fingers. Swelling of the fingers may compromise the patient’s range of motion, including hand grip and fine motor activities. Finger flexion contractures may develop, are typically irreversible, and can be quite severe, especially in patients who have had the diffuse cutaneous form of the disease. Joint contractures may also develop in other small and large joints as sequelae of the skin thickening and tendon friction rubs. Tendon friction rubs may represent a deeper inflammatory and fibrotic process that entraps tendons, often resulting in pain and restriction in joint range of motion (Sandler et al., 2020). Rarely these may result in tendon rupture. Inflammatory arthritis may develop and can be erosive. Other bone, soft tissue, and peripheral nervous system features can compromise hand function, including acro-osteolysis, calcinosis, and median or ulnar neuropathies. Calcinosis may be more extensive, resulting in tumoral or sheet-like deposits throughout soft tissues, and these may be

Suggested Citation:"4 Scleroderma." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
×

exquisitely painful; extrude through the skin, resulting in ulcerations and open wounds; and become infected. Muscle disease or myopathy may also develop in SSc due to inflammation (myositis), microangiopathy, fibrosis, neurologic disease, or malnutrition (Paik, 2018). Depending on the underlying etiology, this can contribute to significant proximal muscle weakness, including of the neck flexors; this in turn can result in fatigue with overhead activities, difficulty rising from a chair or toilet, difficulty in ambulating or climbing stairs, and a dropped head. Cardiac muscle may also be involved, which can result in heart failure, and SSc patients with muscle involvement have a high risk of poor outcomes, including disability and death (Bhansing et al., 2016; Jung et al., 2014; Paik et al., 2016).

Cardiopulmonary Disease

Cardiopulmonary disease is the major driver of morbidity and mortality in SSc and has been estimated to account for 60 percent of all SSc-related deaths (Steen and Medsger, 2007). The complications from cardiopulmonary disease may include exertional or resting dyspnea, paroxysmal nocturnal dyspnea, orthopnea, palpitations, chronic cough, edema and lightheadedness, but patients often have asymptomatic occult disease. The two most common complications are ILD and pulmonary arterial hypertension (PAH).

ILD is the leading cause of death in SSc, accounting for 33 percent of SSc-related mortality in one study (Steen and Medsger, 2007). The prevalence of ILD varies depending on how it is defined, with estimates ranging from 47 to 90 percent using high resolution chest computed tomography (CT) (Distler et al., 2020; Odonwodo et al., 2020). The most common early symptoms are breathlessness, especially on exertion, and a dry cough. The most frequent finding upon physical examination is bilateral inspiratory crackles at the lung bases. Chest radiographs are often normal in mildly symptomatic patients, whereas the single-breath diffusion capacity is the earliest detected abnormality in SSc patients who eventually develop ILD (Khanna and Denton, 2010). High-resolution chest CT is now commonly performed to detect ILD. A small percentage of patients (15 percent) with ILD may experience a decline in pulmonary function during the first 4 years of the disease. ILD progression is usually slow, however, and about 12 percent of scleroderma patients will progress to terminal respiratory failure. ILD that involves more than 20 percent of the lung parenchyma is correlated with poorer survival (Odonwodo et al., 2020).

Pulmonary hypertension (PH) in scleroderma may be due to PAH, associated with left heart disease or ILD. PAH occurs in approximately 12 percent of patients with SSc and is often a later complication of the disease.

Suggested Citation:"4 Scleroderma." 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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PAH is also a major contributor to mortality in SSc due to right ventricular dysfunction and failure (see section on Disease Course below). Serial pulmonary function tests, echocardiograms, and laboratory parameters are important screening tests for identifying PH, and right heart catheterization is required for diagnosis.

It is important to note that SSc can also affect all components of the heart, including the pericardium, myocardium, valves, and conduction system (Hung et al., 2019). Often these cardiac manifestations remain subclinical and may be neglected, yet there is a major unmet need for early detection and intervention strategies. Pericardial manifestations include effusions and pericarditis, which rarely can result in tamponade or constrictive pericarditis. Myocardial disease may be due to inflammation, micro-vascular disease with ischemia-reperfusion injury, or fibrosis. Clinically this may manifest as myocarditis with left ventricular (LV) systolic dysfunction and heart failure with reduced ejection fraction (HFrEF), or diastolic dysfunction and subsequent heart failure with preserved ejection fraction. HFrEF may also develop in the setting of an acute scleroderma renal crisis with a high afterload; LV systolic function may recover in this setting once a renal crisis is adequately managed. Conduction defects (PR prolongation, left anterior fascicular block, and intraventricular conduction defects), arrhythmias (supraventricular tachycardias and ventricular dysrhythmias), and cardiac dysautonomia (impaired heart rate variability) may develop in SSc, and a combination of testing strategies may be required to detect occult disease. Valvular heart disease, including aortic stenosis, has been reported in SSc and may be a contributor to dyspnea. Echocardiography, magnetic resonance imaging, and CT are techniques that are sensitive and enable the early detection of structural and functional SSc-related cardiac pathology. Screening for subclinical cardiac involvement provides an opportunity for early diagnosis and treatment (Lambova, 2014).

Renal Involvement

The pattern of renal involvement may be divided into scleroderma renal crisis (SRC), chronic kidney disease, and inflammatory renal pathology. Of the three renal complications, SRC is the most important and occurs in 10–15 percent of patients with dcSSc; it occurs only rarely (1–2 percent) in patients with limited cutaneous systemic sclerosis (lcSSc) (Khanna and Denton, 2010). Patients with anti-RNA polymerase III antibodies have an increased risk of SRC. The typical features of SRC include new onset of significant systemic hypertension, microangiopathic hemolytic anemia, and decreased renal function (Hudson, 2015). End-stage renal disease requiring dialysis and cardiac decompensation may occur. In approximately 20 percent of patients the diagnosis of SRC precedes the diagnosis of SSc.

Suggested Citation:"4 Scleroderma." 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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Other SRC clinical features include either nonspecific systemic symptoms (headaches, fever, malaise, exertional breathlessness) or signs and symptoms suggestive of end-organ damage (e.g., hypertensive retinopathy and encephalopathy, pulmonary edema, acute renal failure). Before the use of angiotensin-converting enzyme (ACE) inhibitors, SRC was the most common fatal complication of SSc (Odonwodo et al., 2020). Early detection through close blood pressure monitoring and intervention with ACE inhibitors has dramatically changed the course of the disease. Renal recovery is possible with aggressive blood pressure control. In one study, the frequency of scleroderma-related deaths attributed to renal crisis decreased from 42 percent to 6 percent over a 30-year period (Steen and Medsger, 2007).

Other Disease Characteristics

While it is beyond the scope of this review to cover all SSc manifestations in detail, it is important to acknowledge that SSc can have widespread consequences that can affect how patients feel, function, and survive. Often-neglected manifestations of the disease include: periodontal disease including periodontitis, periodontal ligament widening, early dental decay, and tooth loss; bone resorption and avascular necrosis (including atypical areas such as the wrist); acroosteolysis and calcinosis. Additional manifestations such as audiovestibular disease that may result in hearing loss and vertigo; thyroid dysfunction, including hypo- and hyperthyroidism; liver disease, including overlap primary biliary cholangitis or autoimmune hepatitis; lower urinary tract dysfunction resulting in urinary frequency, nocturia, and incontinence; and sexual dysfunction, including dyspareunia and erectile dysfunction are all concomitant conditions (Shah and Wigley, 2008).

Clinical Diagnosis and Professionally Accepted Classification Criteria

A scleroderma diagnosis is based on clinical features and findings, which are heterogeneous and of varying manifestations. Because there is no single diagnostic test to prove the presence or absence of SSc, multiple classification criteria have been proposed to standardize definitions for research studies and clinical trials. The 1980 preliminary ACR criteria for SSc included a major criterion (scleroderma skin thickening proximal to the digits) and minor criteria (sclerodactyly, digital pitting scars, bibasilar pulmonary fibrosis), with the requirement that the one major criterion or at least two minor criteria were required to make a diagnosis of SSc (Subcommittee for Scleroderma Criteria of the American Rheumatism Association, 1980). However, those criteria were formulated using patients with longstanding SSc, and it was believed that patients with early-onset disease

Suggested Citation:"4 Scleroderma." 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 those with limited SSc may remain unclassified and therefore excluded from research studies. That laid the foundation for the development of the current 2013 ACR/European Alliance of Associations for Rheumatology (EULAR) classification criteria (see Table 4-1) (van den Hoogen et al., 2013).

In addition to those classification criteria, others are in use to ensure maximum capture of patients with the disease. These include having at least three of five features of the CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) syndrome. Studies

TABLE 4-1 The ACR/EULAR Criteria for the Classification of Systemic Sclerosis

Item Sub-item(s) Weight*
Skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal joints (sufficient criterion) 9
Skin thickening of the fingers (only count the higher score) Puffy fingers 2
Sclerodactyly of the fingers (distal to the metacarpophalangeal joints but proximal to the proximal interphalangeal joints) 4
Fingertip lesions (only count the higher score) Digital tip ulcers 2
Fingertip pitting scars 3
Telangiectasia 2
Abnormal nailfold capillaries 2
Pulmonary arterial hypertension and/or interstitial lung disease (maximum score is 2) Pulmonary arterial hypertension 2
Interstitial lung disease 2
Raynaud’s phenomenon 3
SSc-related autoantibodies (anticentromere, anti–topoisomerase I [anti–Scl-70], anti–RNA polymerase III) (maximum score is 3) Anticentromere 3
Anti–topoisomerase I
Anti–RNA polymerase III

NOTES: These criteria are applicable to any patient considered for inclusion in an SSc study. The criteria are not applicable to patients with skin thickening sparing the fingers or to patients who have a scleroderma-like disorder that better explains their manifestations (e.g., nephrogenic sclerosing fibrosis, generalized morphea, eosinophilic fasciitis, scleredema diabeticorum, scleromyxedema, erythromyalgia, porphyria, lichen sclerosis, graft-versus-host disease, diabetic cheiroarthropathy).

* The total score is determined by adding the maximum weight (score) in each category. Patients with a total score of ≥ 9 are classified as having definite SSc.

SOURCE: van den Hoogen et al., 2013, with permission.

Suggested Citation:"4 Scleroderma." 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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suggest that patients with Raynaud’s phenomenon who have either or both abnormal nailfold capillaries and a scleroderma-specific autoantibody have a moderate-to-high risk of progressing to definite SSc within 10 years (Koenig et al. 2008). VEDOSS (very early diagnosis of SSc) criteria have also been proposed, including Raynaud’s phenomenon, puffy swollen digits turning into sclerodactyly, abnormal capillaroscopy with scleroderma pattern, and positive anti-centromere or topoisomerase-1 antibodies (Avouac et al., 2011).

Disease Course, Outcomes, and Variability

There is significant heterogeneity in SSc patients’ clinical course and trajectory over time. SSc has the highest case-specific mortality and major morbidity of any of the autoimmune rheumatic diseases. The mortality and morbidity of SSc is typically the result of complications such as cardiopulmonary, renal, or GI involvement (Khanna and Denton, 2010). A major challenge in the field is identifying patients at high risk of disease progression overall and of disease progression in individual organ systems. A study examining the prevalence of organ complications in SSc found that many severe complications, such as cardiac disease, ILD, myositis, and digital ulcers, can each occur in approximately 15 percent of patients (Muangchan et al., 2013). While there is tremendous heterogeneity in the clinical course of SSc, cutaneous subsets and autoantibody type can provide important information about a patient’s potential disease course and prognosis.

Separating patients into the limited and diffuse cutaneous subsets is useful as a risk stratification tool, as patients in these subsets have different risks of complications and internal organ involvement (see Figure 4-2). Patients with diffuse scleroderma have a higher risk of ILD, renal crisis, and cardiac involvement, and those with limited scleroderma have an increased risk of severe GI disease and late-stage complications such as PAH (Denton and Khanna, 2017). However, it is important to note that these complications can develop in patients from either cutaneous subset, highlighting the importance of customizing evaluation and management strategies to the individual patient. Recent data also suggest that finer phenotyping of cutaneous involvement may be valuable in risk-stratifying patients for the risk of internal organ complications. In one study, patients were categorized into four skin subsets. Those with more extensive limited skin involvement had intermediate risks of restrictive lung disease and mortality than those with mild limited skin thickening and those with diffuse disease (Cottrell et al., 2014).

Testing for SSc-specific autoantibodies is another useful tool to risk-stratify patients and to guide monitoring and treatment strategies (see Table 4-2). SSc is

Suggested Citation:"4 Scleroderma." 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 4-2 Usual timing of organ manifestations by clinical subtype in diffuse SSc.
SOURCE: Image courtesy of Drs. Robyn Domsic and Thomas Medsger, University of Pittsburgh Scleroderma Center, with permission.

TABLE 4-2 Phenotypic Characteristics and their Autoantibody Associations in Scleroderma

Autoantibody Phenotype
Centromere proteins B, C Limited cutaneous disease/CREST syndrome
Ischemic digital loss
PAH
Overlap syndromes: Sjögren’s, Hashimoto’s, primary biliary cirrhosis
Topoisomerase I (Scl-70) Diffuse > limited cutaneous disease
ILD
African-Americans
RNA polymerase III Rapidly progressive diffuse cutaneous disease, contractures
Contemporaneous cancer with disease onset
Renal crisis (25–33%)
Myopathy and cardiac disease
GAVE
Suggested Citation:"4 Scleroderma." 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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Autoantibody Phenotype
U1-RNP Limited > diffuse cutaneous disease
SLE overlap
Inflammatory arthritis
Myositis overlap
PAH
ILD
African-Americans
U3-RNP (fibrillarin)* Diffuse > limited cutaneous disease
PAH
ILD
Cardiac and skeletal muscle disease
Small bowel involvement
African-Americans
B23* PAH
PM/Scl Limited > diffuse cutaneous disease
Myositis overlap
Acro-osteolysis
ILD
Th/To* Limited cutaneous disease
ILD
PAH
Small bowel involvement
U11/U12 RNP* ILD
Ku* Limited cutaneous disease
Myositis

NOTES: CREST = calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia; GAVE = gastric antral vascular ectasia; ILD = interstitial lung disease; PAH = pulmonary arterial hypertension; RNP = ribonucleoprotein.

* These antibodies are not easily or commercially available at present.

SOURCE: Shah and Wigley, 2013, with permission.

Suggested Citation:"4 Scleroderma." National Academies of Sciences, Engineering, and Medicine. 2022. Selected Immune Disorders and Disability. Washington, DC: The National Academies Press. doi: 10.17226/26595.
×

associated with several autoantibodies, which are associated with distinct clinical phenotypes. Anti-centromere antibodies (ACAs) and anti-Sci-70 antibodies are useful in distinguishing patients with systemic sclerosis from healthy controls, from patients with other connective tissue disease, and from unaffected family members (Ho and Reveille, 2003). For example, ACAs often predict limited skin involvement and the absence of SSc-ILD, whereas the presence of anti-Scl-70 antibodies increases the risk for diffuse skin involvement and SSc-ILD. Although anti-fibrillarin autoantibodies and anti-RNA-polymerase III autoantibodies occur less frequently, they are also predictive of diffuse skin involvement and systemic disease. Patients with anti-RNA polymerase III antibodies also have a higher risk of renal crisis and of having an underlying malignancy (Igusa et al., 2018). The antinuclear antibody assay (ANA test) is almost always positive in rheumatic diseases such as lupus, RA, dermatomyositis, and scleroderma. Since the test can be positive in many of those diseases, it is not diagnostic for any one particular disease.

As previously noted, skin fibrosis is a hallmark feature of SSc. In patients with more extensive lcSSc or dcSSc, the skin disease may worsen within the first 3 years of disease onset. This may be followed by a period of stabilization and later softening of the skin. Patients with early diffuse SSc typically have worsening skin thickness over the first 1–3 years after disease onset and may develop internal organ involvement during this time. Worsening skin thickness is a predictor of morbidity and mortality. After 1–3 years of worsening skin thickness, the skin can stabilize and may have a variable degree of softening. While this may occur independently of treatment, the goal of immunosuppressive and antifibrotic therapies is to accelerate the pace of improvement, result in less cumulative damage, and prevent joint contractures and disability. Softening of skin is associated with improved survival, although that relationship is not straightforward.

An important study by Steen and Medsger (2007) demonstrated that the two most common causes of SSc-related death in the modern era are ILD and PAH (Steen and Medsger, 2007). As described above, ILD is commonly detected by high-resolution chest CT in patients with SSc, but only a subset of patients have progressive lung disease. A recent study (Hoffmann-Vold et al., 2020), using data from the European Scleroderma Trials and Research (EUSTAR) database, examined overall disease course, the progression of patterns, and risk factors for progressive ILD in patients with SSc–associated ILD. The findings indicated that most patients with SSc-ILD had a slow pattern of decline in lung function, with more periods of stability than decline (58 percent). However, 34 percent of the patients showed a progressive pattern, with more periods of decline than stability and only 8 percent of patients showed a rapidly declining forced vital capacity (FVC) pattern, with consecutive episodes of FVC decline and no

Suggested Citation:"4 Scleroderma." 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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periods of FVC stability or improvement. Patterns of progression in patients with moderate, significant, and major overall decline in FVC percent are shown in Figure 4-3 below.

PAH occurs in up to 15 percent of patients with SSc. It has been recognized that early detection strategies are important in improving long-term survival. Routine screening with an assessment of patient symptoms, pulmonary function testing, echocardiography, and N-terminal pro hormone B–type natriuretic peptid (NT-proBNP) testing may identify patients with emerging pulmonary vascular disease at an earlier stage of the disease. Exercise provocation may also play a role in assessing for exercise-induced pulmonary hypertension that may be a precursor to resting PAH. While there are many U.S. Food and Drug Administration (FDA)-approved therapies for PAH (see Treatment section below), survival remains poor. In a multicenter French study of 546 SSc patients undergoing routine pulmonary

Image
FIGURE 4-3 Patterns of disease course in systemic sclerosis–interstitial lung disease.
NOTES: Overall disease course was evaluated by determining the magnitude of forced vital capacity (FVC) changes (% predicted) in individual patients from baseline to the end of follow-up defined as follows: major decline (FVC decline of > 20%); significant decline (FVC decline of 10% to 20%); moderate decline (FVC decline of 5% to 10%); stable (FVC decline or improvement of < 5%); and improvement (FVC improvement of ≥ 5%). Patterns of disease progression are shown in patients with improved FVC and stable FVC and those with significant or major decline.
SOURCE: Hoffmann-Vold et al., 2021, with permission.
Suggested Citation:"4 Scleroderma." 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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hypertension screening, 47 patients had PAH at baseline. Twenty patients died during follow-up, giving a 3-year survival of 56.3 percent (Hachulla et al., 2009). When compared to patients with idiopathic PAH, patients with SSc-PAH have poorer survival. In the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) registry, 641 patients with connective tissue disease (CTD)-PAH (399 with SSc) were compared with 1,251 patients with idiopathic PAH (Chung et al., 2010). While the CTD-PAH group had better pulmonary hemodynamics than the idiopathic group, they had lower 1-year survival rates (86 percent vs 93 percent) and were more likely to be hospitalized. Patients with SSc-PAH in particular had lower 1-year survival rates compared with other forms of CTD-PAH: 82 percent in SSc versus 94 percent in SLE, 88 percent in mixed connective-tissue disease, and 96 percent in RA.

Data suggest that with a focus on early detection strategies, survival rates are improving. In the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) registry, survival was assessed in 160 patients with incident SSc-PAH and was 95 percent, 75 percent, 63 percent, and 49 percent at 1, 3, 5, and 8 years, respectively (Kolstad et al., 2018). When restricted to deaths due to PAH, survival rates were 97 percent, 83 percent, 76 percent, and 76 percent, respectively. In a French study, two incident cohorts of patients with SSc-PAH were studied, one a routine practice cohort and the other consisting of SSc patients who entered a systematic PAH detection program (Humbert et al., 2011). At the time of PAH diagnosis, those in the early-detection program had less advanced PAH including better functional class, lower mean pulmonary arterial pressures and pulmonary vascular resistance index, and better cardiac output. PAH-specific therapies were used in both groups, but survival was much better in the early-detection group: 100 percent versus 75 percent at 1 year, 81 percent versus 31 percent at 3 years, 73 percent versus 25 percent at 5 years, and 64 percent versus 17 percent at 8 years. These studies highlight the importance of early detection and intervention for PAH in patients with SSc.

The prognosis of SSc renal crisis has improved significantly over time due to the use of ACE inhibitors. Steen and colleagues examined the outcomes of SSc renal crisis before and after the availability of ACE inhibitors (Steen and Medsger, 2000). One-year survival was 15 percent in patients who did not receive ACE inhibitors, compared with 76 percent in those who did. Even among those who were treated with ACE inhibitors, 44 percent died early or required permanent dialysis. Older age and congestive heart failure were risk factors for these poor outcomes. Importantly, renal recovery is possible in patients with renal crisis. Fifty-five percent of patients who survived dialysis more than 3 months and continued ACE inhibitor therapy were able to discontinue dialysis 3–15 months later,

Suggested Citation:"4 Scleroderma." 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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whereas none of the patients on dialysis without ACE inhibitor therapy were able to discontinue dialysis. A subsequent study examined a larger sample of 145 patients with renal crisis treated with ACE inhibitors (Steen and Medsger, 2000). Thirty-eight percent of patients did not require dialysis, 23 percent required temporary dialysis, and 39 percent had poor outcomes including permanent dialysis or death. Importantly, more than 50 percent of patients who started dialysis were able to discontinue it 3–18 months later. Over a 30-year time period, the frequency of deaths due to renal crisis has decreased dramatically, from 42 percent of SSc-related deaths to 6 percent (Steen and Medsger, 2000).

The GI tract is the most commonly involved internal organ system in SSc, and gastroesophageal manifestations are the most frequently occurring GI-related SSc manifestation. Although GI involvement is common and has a major impact on an individual’s quality of life, only a minority of cases have life-threatening complications. Severe GI dysmotility, particularly of the small bowel, may contribute to malnutrition and the requirement of total parenteral nutrition (McMahan et al., 2020). Acute intestinal pseudo-obstruction may also be associated with the need for surgical resection, the use of total parenteral nutrition, and mortality (Mecoli et al., 2014). In a case-control study using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample, 5.4 percent of SSc hospitalizations were associated with intestinal pseudo-obstruction, with an in-hospital mortality of 7.3 percent (Valenzuela et al., 2016). In a study examining changes in mortality over time in SSc, 4 percent of all SSc-related deaths were found to be due to GI complications (Steen and Medsger, 2007).

Beyond these severe cardiopulmonary, renal, and GI manifestations that are associated with increased mortality, it is important to note that many clinical features of the disease can contribute to functional impairments (see additional details below).

SSc patients may have a normal life expectancy. There may be periods of time when the condition stabilizes, and there may be some improvement in skin and mobility. A recent study (Kennedy et al., 2018) found that the 30-year survival rate had improved for females but not for male patients, and that patients with diffuse and overlap disease continued to display early mortality. Further, no disease-modifying drugs have been consistently found to alter disease course.

TREATMENT AND MANAGEMENT

Because of the heterogeneity of scleroderma and potential treatment toxicity, therapy must be individualized to each patient’s clinical presentation. No disease-modifying agent has been proven to prevent or reverse

Suggested Citation:"4 Scleroderma." 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 overall disease process. While there are no FDA-approved medications for the overall disease, many therapies have been demonstrated to be beneficial in observational studies and randomized controlled trials, and these constitute the current standard of care. Additionally, there are now FDA-approved therapies for organ-specific complications of scleroderma, including ILD and PAH. While it is beyond the scope of this report to cover all potential therapies for the various manifestations of SSc, we present detailed information about therapies for the most common disabling manifestations of the disease, including Raynaud’s phenomenon, active cutaneous disease, ILD, and PAH. Table 4-3 below summarizes these therapies in addition to treatment options for the GI and renal manifestations of the disease. Treatments for inflammatory myositis and arthritis are similar to those used in the idiopathic inflammatory myopathies and RA, as described in chapters 5 and 6.

Therapies for Manifestations of Systemic Sclerosis

Raynaud’s Phenomenon Therapeutics

Both non-pharmacologic and pharmacologic interventions play a role in the effective management of Raynaud’s phenomenon (Wigley and Flavahan, 2016). Cold avoidance remains one of the most effective therapies here, and in addition to avoiding cold triggers, active measures for systemic and local warming are critical, including wearing multiple layers of clothes, hats, gloves, wool socks, and insulated shoes such as fur lined boots. The use of local measures such as using chemical or electric hand warmers can help prevent or resolve acute attacks. Drug therapy is often required in scleroderma-associated Raynaud’s phenomenon to reduce the frequency and severity of Raynaud’s attacks and improve an individual’s quality of life. The first line of therapy is initiating a long-acting dihydropyridine calcium channel blocker, as these drugs are moderately effective in reducing attack frequency. If patients have side effects (such as significant edema, headache, lightheadedness, or hypotension), inadequate response, or severe disease such as persistent digital ischemic lesions, other agents are often considered. For patients with mild to moderate disease who cannot tolerate calcium channel blockers, phosphodiesterase-5 (PDE-5) inhibitors, a topical nitrate, an angiotensin II receptor blocker, a selective serotonin reuptake inhibitor (SSRI), or pentoxifylline should be considered. For patients with digital ulcers or other ischemic lesions, combination therapy may be required. Often patients are managed with a calcium channel blocker and PDE-5 inhibitors, and antiplatelet therapy (such as aspirin) may be added. If there are recurrent severe events, endothelin receptor antagonists are often added, and if there is critical digital ischemia, infusions of prostacyclin analogs

Suggested Citation:"4 Scleroderma." 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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may be required. Some patients poorly tolerate vasodilator therapy, and SSRIs or pentoxifylline may be better tolerated in these patients. Finally, it is important to note there is some geographic variability in Raynaud’s management. Cyclic infusions of prostacyclin analogs are often used in Europe to manage Raynaud’s phenomenon independent of digital ischemic lesions; as of this writing, clinical trials are investigating this in the United States.

Therapeutics for Active Cutaneous Disease

A key aspect of scleroderma management is determining whether clinical features reflect disease activity or reflect damage. For patients with more extensive limited scleroderma or diffuse cutaneous disease, the signs of cutaneous disease activity include progressive skin thickening involving new body areas, worsening skin thickening in previously affected body areas, persistent and severe pruritis—often with a neuropathic discomfort to the skin—and tendon friction rubs. The therapeutic approach chosen may depend on whether there is evidence of disease activity in other organs, such as ILD, myopathy, or inflammatory arthritis.

Mycophenolate mofetil (MMF) is often the first-line therapy for active cutaneous disease, based on data from observational studies and randomized controlled clinical trials where the skin was assessed as a secondary outcome. In an observational study, 98 patients with active diffuse cutaneous scleroderma who were treated with MMF were compared with historical controls from three negative multicenter randomized clinical trials (Le et al., 2011). Improvements in the mRSS were observed at as early as 3 months and continued through 12 months of follow-up. Compared with historical controls, the mRSS was significantly lower by the 12-month time point. There were also improvements in quality-of-life measures, and pulmonary function remained stable. In the Scleroderma Lung Study II (SLS II), patients with scleroderma and ILD were randomized to receive either 24 months of MMF or 12 months of daily oral cyclophosphamide followed by 12 months of placebo (Tashkin et al., 2016). Declines in mRSS were comparable between the MMF and cyclophosphamide arms of the study, and 71.7 percent of patients treated with MMF were classified as improvers with respect to cutaneous disease. MMF had a better tolerability profile than cyclophosphamide in this study. In patients with milder but active skin disease, methotrexate is also a consideration (Pope et al., 2001; van den Hoogen et al., 1996).

In patients with inadequate response to first-line therapy with MMF or methotrexate, other agents may be considered and used singly or in combination. Potential treatment options could include adding intravenous immunoglobulin (IVIG) therapy to MMF or methotrexate, combining MMF with methotrexate, switching to daily oral cyclophosphamide, adding rituximab,

Suggested Citation:"4 Scleroderma." 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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or trying an experimental therapy. In severe cases, high-dose immunoablative cyclophosphamide or stem cell transplantation may be considered. The choice of therapy is often influenced by whether there are other manifestations of disease activity.

In an observational study of patients with refractory, active diffuse cutaneous scleroderma, the addition of IVIG resulted in significant improvements in mRSS over time, and tendon friction rubs resolved in most patients in whom they were present at baseline (Poelman et al., 2015). Muscle strength and creatine kinase levels also improved in patients who had features of myopathy. IVIG may be considered in patients who do not improve with MMF monotherapy, have tendon friction rubs, and have concomitant myopathy.

In the Scleroderma Lung Study I (SLS I), patients with scleroderma and ILD were randomized to daily oral cyclophosphamide versus placebo for 1 year (Tashkin et al., 2006). While not the primary outcome measure, skin scores were found to have decreased more on average in patients treated with cyclophosphamide than with placebo. Given the side-effect profile of cyclophosphamide, including cytopenias, infection, hemorrhagic cystitis, and later risk of malignancy, one strategy is treatment with cyclophosphamide for 6–12 months and then transitioning to another agent such as MMF for maintenance immunosuppression. Cyclophosphamide may be considered in patients with concomitant ILD also.

Rituximab has largely been evaluated in observational studies, with initial results suggesting improvement in cutaneous disease (Aggarwal et al., 2017; Daoussis et al., 2012). Rituximab is a reasonable consideration in patients with active diffuse disease who have failed first-line therapy and who have other features for which rituximab may exert a benefit, such as ILD, inflammatory arthritis, and myopathy.

In severe and refractory cases, there may be a role for stem cell transplantation. Two multicenter clinical trials have evaluated transplantation regimens in Europe and the United States. In the Autologous Stem Cell Transplantation Internal Scleroderma (ASTIS) trial, 156 patients with diffuse SSc were randomized to high-dose immunosuppressive therapy (IV cyclophosphamide, rabbit antithymocyte globulin, IV methylprednisolone) and autologous hematopoietic stem cell transplantation versus monthly IV cyclophosphamide (van Laar et al., 2014). While there was elevated treatment-related mortality in the first year, there was an overall long-term event-free survival benefit in patients treated with transplantation. In the U.S. Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, patients with severe scleroderma were enrolled and randomized to myeloablative autologous stem cell transplantation versus cyclophosphamide (Sullivan et al., 2018). Diffuse cutaneous disease was not a requirement for enrollment, but study patients had elevated baseline mean mRSS consistent

Suggested Citation:"4 Scleroderma." 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 diffuse disease. The primary endpoint in this trial was the global rank composite score (GRCS) which factored in multiple disease manifestations simultaneously. Patients in the transplantation arm were more likely to improve with respect to mRSS and had better GRCS scores as well as longer overall and event-free survival.

Interstitial Lung Disease Management

The first-line therapy for scleroderma-ILD includes MMF, based on data from the SLS II trial. Patients were randomized to MMF versus cyclophosphamide as described above. The adjusted FVC percent predicted improved by comparable amounts in both groups over 24 months. As patients on cyclophosphamide were more likely to have leukopenia and shorter times to withdrawal from the study drug or treatment failure, mycophenolate has become first-line therapy for scleroderma ILD. However, in patients failing therapy with mycophenolate, data from the SLS I clinical trial indicate that cyclophosphamide may be a reasonable consideration.

Importantly, there are now two FDA-approved agents for scleroderma ILD, nintedanib and tocilizumab. In the Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial, 576 patients with SSc ILD were randomized to nintedanib or placebo (Distler et al., 2019). Background therapy was allowed, and 48.4 percent of patients were on mycophenolate at baseline. The rate of decline in pulmonary function, as measured by the adjusted annual rate of change in FVC, was the primary outcome of interest. The rate of decline was less in the nintedanib arm (-52.4 mL/year) than in the placebo (-93.3 mL/year). The rate of change did vary by baseline mycophenolate use: mycophenolate + nintedanib was -40.2 mL/year, mycophenolate + placebo was -66.5 mL/year, nintedanib without mycophenolate at baseline was -63.9 mL/year, and placebo without mycophenolate at baseline was -119.3 mL/year. Notably, there were no improvements in mRSS or dyspnea in the trial. Diarrhea was a common adverse event, occurring in 75.7 percent in the nintedanib arm and 31.6 percent in the placebo arm. It will be important to see how practice patterns change with this new approval. Currently, MMF remains first-line therapy for many providers, given the comparable rates of decline in pulmonary function between the mycophenolate-alone arm and the nintedanib-alone arm. Additionally, mycophenolate may have therapeutic benefit for active cutaneous and muscle disease and may be better tolerated than nintedanib. There may be a role for upfront combination therapy in patients with a high risk of ILD progression.

Tocilizumab is another agent that has recently received FDA approval for use with SSc ILD. This drug was studied in a phase 3, randomized,

Suggested Citation:"4 Scleroderma." 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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double-blind, placebo-controlled trial for diffuse skin disease and did not require the presence of ILD for enrollment (Khanna et al., 2020). The trial did not meet its primary endpoint for skin disease, but a secondary analysis among patients with SSc ILD demonstrated that the change in FVC percent predicted over 48 weeks was less in the tocilizumab arm than in the placebo arm. These data suggested that tocilizumab could have a role in preserving lung function in patients with early SSc ILD and high acute phase reactants. This drug may be attractive for use in patients with concomitant inflammatory arthritis or tendon friction rubs.

Pulmonary Arterial Hypertension Management

There have been significant advances in PAH management over the past few decades (Galiè et al., 2015) with numerous drugs that are now FDA-approved. The objectives of therapy are to improve exercise capacity, the quality of life, and right ventricular function while lowering mortality risk. Phosphodiesterase 5 inhibitors, endothelin receptor antagonists, prostacyclin analogs, a prostacyclin receptor agonist, and a soluble guanylate cyclase stimulator are available in the therapeutic armamentarium. Most clinical trials of these agents have included patients with both idiopathic PAH and CTD-PAH, including patients with SSc. In general, these studies have demonstrated an improvement in 6-minute walk distance, which is an imperfect marker in patients with SSc given that patients with the disease often have musculoskeletal involvement that may limit ambulation. There is now a movement to perform longer-duration clinical trials in PAH with a focus on composite morbidity and mortality endpoints (Thakkar and Lau, 2016).

Those and other therapies for varied SSc manifestations are detailed in Table 4-3.

Likelihood of Improvement with Treatment

Scleroderma is a multisystem disease with variable expression, thus any treatment plan must be holistic yet at the same time focus on the dominant organ disease. It is important to carefully characterize patients with scleroderma and SSc and to identify the specific manifestations and level of disease activity to decide on the appropriate treatment. That is particularly important in the management of scleroderma and SSc because there is no treatment that has been proven to modify the overall disease course, although therapy that targets specific organ involvement early, before irreversible damage occurs, does improve both the quality of life and survival.

The goal of therapy is to improve the quality of life by minimizing specific organ involvement and subsequent life-threatening disease. At the

Suggested Citation:"4 Scleroderma." 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 4-3 Treatments for Organ-Specific Complications of Systemic Sclerosis

Complication Treatment
Raynaud’s phenomenon α-adrenergic blockers
Angiotensin-II receptor blockers
Long-acting calcium channel blockers (dihydropyridines)
Phosphodiesterase 5 inhibitors
Endothelin receptor antagonists
Prostacyclin analogs
Pentoxifylline
Stellate ganglionic blockades, digital sympathectomy
Skin fibrosis Immunomodulatory drugs (methotrexate, mycophenolate mofetil [Cellcept], cyclophosphamide [Cytoxan], intravenous immunoglobulin [IVIG], rituximab, stem cell transplantation)
Gastroesophageal reflux disease Antacids
Histamine H2 blockers
Proton pump inhibitors
Intestinal dysmotility or bacterial overgrowth Antibiotics
Correction of nutritional deficiencies
Promotility agents
Pulmonary fibrosis or alveolitis Immunomodulatory drugs (mycophenolate mofetil, cyclophosphamide, rituximab, tocilizumab)
Anti-fibrotic medications (nintedanib, pirfenidone)
Pulmonary arterial hypertension Diuretics
Endothelin-1 receptor inhibitors (bosentan [Tracleer], ambrisentan)
Oxygen
Phosphodiesterase-5 inhibitors (sildenafil [Revatio], tadalafil)
Prostacyclin analogues (epoprostenol [Flolan], treprostinil [Remodulin], iloprost [Ventavis])
Warfarin (Coumadin) is sometimes used in patients with recurrent pulmonary thromboembolic disease secondary to pulmonary arterial hypertension
Scleroderma renal crisis Dialysis
Angiotensin-converting enzyme inhibitors

SOURCE: Reprinted with permission from Hinchcliff and Varga, 2008.

Suggested Citation:"4 Scleroderma." 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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same time the many factors that alter daily function need to be addressed, including nutrition, pain, deconditioning, musculoskeletal disuse, comorbid conditions, and the emotional aspects of the disease such as fear, depression, and the social withdrawal caused by disfigurement (Shah and Wigley, 2013). Secondary impairments resulting from scleroderma and its treatments and treatment availability are discussed in Chapter 2.

Select Treatments Currently in Clinical Trials

There are many clinical trials in progress for therapeutic interventions for scleroderma and SSc. Barriers to drug development in SSc include disease heterogeneity, inadequate trial size or duration, the management of background medications, and imperfect outcome measures. The National Institutes of Health’s (NIH’s) National Library of Medicine website (https://clinicaltrials.gov/ct2/home) may be used to find clinical trials. A search on the NIH website for scleroderma conducted on October 22, 2021, listed 197 studies for systemic sclerosis or scleroderma. The committee used the following criteria when searching for scleroderma studies: all studies, United States only, all ages.

The committee found that clinical trials are under way to study potential therapies for most manifestations of the disease, including immunosuppressive or immunomodulatory, anti-fibrotic, and vascular therapies. However, while there are no therapies that cure scleroderma, there is ongoing interest in stem cell transplantation to treat severe manifestations of the disease more globally. In addition, rehabilitation and complementary medicine strategies are being investigated to improve functional status in patients with SSc.

DISEASE-SPECIFIC FUNCTIONAL LIMITATIONS

Patients with SSc may develop functional impairment due to skin thickening, small and large joint contractures, inflammatory arthritis, tendon friction rubs, myositis, digital ulcers, GI dysmotility, and dyspnea from cardiopulmonary complications. Skin thickening, joint contractures, synovitis, and digital ulcers in particular may contribute to hand disability.

Functional impairment may be assessed by a number of metrics, the most common of which is a scleroderma modification to the Health Assessment Questionnaire–Disability Index (SHAQ-DI). In the DeSScipher multinational, longitudinal study, data from five observational trials focusing on digital ulcers, hand arthritis, ILD, pulmonary hypertension, and severe cardiac disease were included; 944 of the cohort patients had SHAQ data collected to assess functional disability; 59 percent, 34 percent, and 7 percent of patients had mild–moderate, moderate–severe, and severe to very

Suggested Citation:"4 Scleroderma." 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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severe disability, respectively (Jaeger et al., 2018). Dyspnea, muscle weakness, digital ulcers, and GI symptoms (esophageal, stomach and intestinal) were associated with disability. Patients with diffuse SSc had higher disability scores than those with limited SSc.

In another study of patients with diffuse SSc from the EUSTAR database, baseline severity of skin thickening as assessed by the mRSS was an important predictor of subsequent disability (Allanore et al., 2020). In a study of 402 SSc patients followed at the Salford Royal NHS Foundation Trust, increased mRSS was associated with worsening disability in patients with early (disease duration < 5 years) diffuse SSc, but not in those with late diffuse SSc, early limited SSc, or late limited SSc (Peytrignet et al., 2019). Pruritus may contribute to disability and impaired physical and mental functioning, as shown in a Canadian Scleroderma Research Group study (El-Baalbaki et al., 2010).

In a multicenter longitudinal study of 745 SSc patients in the Canadian Scleroderma Research Group registry, disability worsened over time (Schnitzer et al., 2011). Diffuse disease and breathing problems were strong predictors of disability. Additionally, time-dependent covariates for Raynaud’s, finger ulcers, GI, and breathing problems were all significantly associated with increased disability as assessed by the HAQ.

In the Johns Hopkins Scleroderma Center cohort, 22.8 percent of the 1,718 patients assessed had muscle weakness (Paik et al., 2016). Patients with muscle weakness had multiple features of severe disease, including diffuse skin involvement, synovitis, and restrictive ventilatory defect on pulmonary function testing. The degree of muscle weakness was associated with the severity of disability in this study.

A frequent manifestation of SSc is digital ulcers (DUs). Guillevin et al. (2013) conducted a study on functional impairment in patients with SSc and DUs. The authors made assessments from the Digital Ulcer Outcome Registry, an international, multicenter, observational registry of SSc patients with DU disease. The study included 2,327 patients who completed a DU-specific functional assessment questionnaire with a 1-month recall period, measuring impairment in work and daily activities and hours of help needed from others. Physician-reported clinical parameters were used to describe the population. The study authors found that with increasing number of digital ulcers, SSc patients reported increased impairment in work and daily activities and needed more support from others.

In a cross-sectional, multicenter study from the Canadian Scleroderma Research Group registry, 643 patients were assessed to identify predictors of work disability (Hudson et al., 2009). Twenty-one percent of patients in this cohort were work disabled. Work disability was reported early in the disease and increased with longer disease duration. Of work-disabled individuals younger than 65 years of age, 28 percent had a disease duration

Suggested Citation:"4 Scleroderma." 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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of less than 2 years and 44.8 percent had a disease duration of 10–15 years. Comorbidities, disease duration, diffuse disease, disease severity, pain, fatigue, and impaired physical function were all correlated with work disability.

In a Spanish study, investigators estimated the SSc-related burden of disease using procedures in the Global Burden of Disease study (Villaverde-Hueso et al., 2007). Disability-adjusted life-years (DALYs) were calculated as the sum of years of life lost and years lived with disability. SSc-related DALYs totaled 1,732 life-years, with 73 percent being accounted for among individuals aged 15–54 years. Sixty-eight percent of DALYs were accounted for by years lived with disability, compared with 32 percent due to years of life lost.

Appropriate rehabilitation therapy is an important tool to cope with disability (Maddali-Bongi and Del Rosso, 2016). This may include physical therapy, occupational therapy with particular attention to hand function, and cardiopulmonary rehabilitation. Despite these services’ potential to improve function, data suggest that these services may be underused in the care of patients with SSc (Becetti et al., 2019). In a study including 1,627 patients from the Scleroderma Patient-Centered Intervention (SPIN) cohort, only 23 percent of patients had used physical and occupational therapy (PT/OT) in the preceding 3 months. PT/OT use was associated with higher education, having moderately severe small joint contractures, severe large joint contractures, fewer digital ulcerations, and higher disability and pain scores. PT/OT use was lowest in patients from the United States.

JUVENILE SCLERODERMA

Juvenile scleroderma (localized and systemic sclerosis) is rare, with an estimated prevalence of 3–30 per 1 million children (Beukelman et al., 2018). In children, the most prominent feature of the systemic form is skin manifestations, followed by musculoskeletal and vascular involvement. Cardiovascular, GI, and renal disorders are rare. Linear scleroderma is the most common subtype in childhood, with most cases presenting in the first decade of life.

Localized scleroderma frequently involves the deeper subcutaneous tissues, muscles, joints, and even bone (Zulian et al., 2005). Severe deformities, including extremity leg length discrepancies and facial atrophy, may occur, with damage persisting into adulthood. Linear scleroderma can be associated with extracutaneous manifestations and long-term sequelae (Peña-Romero and Garcíá-Romero, 2019). In children the most prominent features of the systemic form of scleroderma are skin manifestations followed by musculoskeletal and vascular involvement.

Suggested Citation:"4 Scleroderma." 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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Cardiovascular, GI, and renal involvement may also be seen. Recent studies have shown that ILD is more common than previously thought (Foeldvari et al., 2020).

Combinations of disease-modifying anti-rheumatic drugs (such as methotrexate, MMF, and cyclosporine) and steroids are considered first-line therapies. In the most severe forms, biologic treatments are useful. Methotrexate is considered a first-line treatment for localized scleroderma. Recently investigators from the Childhood Arthritis and Rheumatology Research Alliance presented results of a 1-year observational cohort study comparing three methotrexate-based regimens (Li et al., 2020). Most children demonstrated response to all regimens (Kurzinski et al., 2019; Li et al., 2020). There was some damage accrual, however. Few prognostic studies have been conducted in children, but findings suggest that the disease runs a chronic or intermittent–recurrent course and frequently causes sequelae (Aranegui and Jiménez-Reyes, 2018). Martini et al. (2018) conducted a retrospective and cross-sectional study in pediatric patients with juvenile localized scleroderma. The disease course was drawn from a retrospective analysis of patients’ clinical features, treatment, and disease course and outcome at last evaluation. Disease activity and the severity of tissue damage were assessed using thermography and the Localized Scleroderma Cutaneous Assessment Tool. After 10 years of follow-up, findings indicated that 12.5 percent of the patients, all with linear subtype, still had active disease. At least one disease relapse occurred in 22.2 percent of the patients, and the first flare was observed 20 months after the first treatment was discontinued. Mild tissue damage was observed in more than half of the patients, moderate damage in 25.4 percent, and severe in 23.0 percent, and 19.8 percent presented with a functional limitation. The levels of functional disability have been shown to be higher in juvenile SSc than those observed in patients with other childhood-onset rheumatic diseases (Stevens et al., 2018). The delay in the start of systemic treatment was associated with longer disease activity and higher relapse rate (Martini et al., 2018). The presence of ANAs and older age at onset have also been shown to predict disease relapse (Kurzinski et al., 2019).

SUMMARY

Systemic sclerosis, also called scleroderma, is a complex, multisystem rheumatic condition which has high variability in disease presentation and trajectory. It is characterized by immune dysregulation, vasculopathy, and progressive fibrosis that typically affects the skin and internal organs. Internal organ involvement can be minimal, ranging from mild gastroesophageal reflux, subtle skin changes, and Raynaud’s phenomenon to severe and fulminant multisystem disease with ILD, severe digital ischemia, severe GI

Suggested Citation:"4 Scleroderma." 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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dysmotility, myopathy, renal crisis, and pulmonary hypertension. Patients with SSc may develop functional impairment due to skin thickening, small and large joint contractures, inflammatory arthritis, tendon friction rubs, myositis, digital ulcers, GI dysmotility, and dyspnea from cardiopulmonary complications. Skin thickening, joint contractures, synovitis, and digital ulcers in particular may contribute to hand disability. SSc has the highest case-specific mortality and major morbidity of any of the autoimmune rheumatic diseases. The mortality and morbidity of SSc is typically the result of such complications as cardiopulmonary, renal, GI, and peripheral vascular involvement, and ILD and pulmonary hypertension are the most common causes of death.

Although SSc can affect adults at any age, the peak onset is between 40 and 50 years old, and the disease occurs more frequently in women. Scleroderma may also be more severe in African Americans and Native Americans. Early diagnosis might improve patient outcomes, and treatment strategies are aimed at halting the progression of complications. Autoantibodies and skin subtype may identify patients at high risk of specific complications and are useful for diagnosis and disease classification. Frequent monitoring through physical examination, laboratory testing, and serial pulmonary function testing and echocardiogram assessments can identify patients with complications at an early stage, offering an opportunity for an intervention that may improve the prognosis.

There are no current conventional treatments that are effective in stopping or reversing the overall course of SSc. Several medications have been demonstrated to slow the progression of the disease or to reduce the development of new symptoms, at least in the short term. In addition to medications that are used to treat individual symptoms, some medications may interrupt the disease process in a variety of ways. Immunosuppressive drugs, used alone or in combination, may be used to control disease activity and slow the progression of the disease, particularly for patients with active cutaneous, pulmonary, and musculoskeletal manifestations. Vasoactive medications and drugs targeting GI manifestations are also commonly used. In addition to monitoring for and treating organ-specific complications, a holistic approach is needed to address the many aspects that can affect an individual’s quality of life, such as pain, musculoskeletal disease, deconditioning, nutrition, disfigurement, depression, and anxiety. Although there are no treatments that will cure scleroderma, there are many treatment options to improve both quality of life and survival.

Juvenile scleroderma is rare in children and is characterized by a stiffening of the skin. The disease is divided into two main forms—systemic and localized scleroderma. Skin manifestations are the most prominent feature of the systemic form, followed by musculoskeletal and vascular

Suggested Citation:"4 Scleroderma." 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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involvement. A combination of steroids and disease-modifying anti-rheumatic drugs represent the first line of therapies to treat scleroderma in children. In the most severe forms, biologic treatments are useful.

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Suggested Citation:"4 Scleroderma." 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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