Juvenile Systemic Sclerosis

Genetics

The genetic load for SSc appears to be lower than for other autoimmune diseases. The concordance rate for adult-onset SSc in twins is low (5.6% for dizygotic, 4.2% for monozygotic), and familial history of autoimmune disease is less common than with other autoimmune diseases. Approximately 15% to 20% of patients with SSc have a first-degree relative with conditions such as psoriasis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren syndrome, thyroiditis and, less commonly, SSc and LS. ^,

Familial occurrence of JSSc is rare, but cases have been reported in a mother and her 6-year-old son, in two sisters ages 12 and 16 years, and in monozygotic twins. However, there is evidence for a genetic contribution to pathogenesis. Familial clustering has been described, with first-degree relatives of patients with SSc carrying a 10- to 16-fold relative risk for disease and siblings carrying a 10- to 27-fold risk. In families with more than one case of SSc, affected individuals shared cutaneous subsets of disease severity and SSc-associated autoantibodies, with similar ages of onset. However, the genetic predisposition for loss of immune self-tolerance is high, especially for antinuclear antibodies in monozygotic compared with dizygotic twins (90% vs. 40%). Some of the discordance in disease penetrance may be attributed to differential methylation of X-encoded genes. Finally, gene expression studies in cultured dermal fibroblasts from twins suggest a heritable profibrotic program.

Numerous studies have reported the largest contributor to genetic risk for SSc lies in the HLA locus. HLA alleles found associated with adult SSc have also been associated with JSSc. For example, patients with JSSc-dermatomyositis overlap had an increased frequency of DQA1∗05 and DRB1∗03 and a trend toward decreased DRB1∗15. An HLA study conducted in JSSc reported unique HLA-DR and HLA-DQ findings compared with adult-onset SSc. There was no association with the allele most closely associated with adult-onset SSc, HLA DRB1∗11, nor with the specific alleles DRB∗1101 or ∗1104. Although subanalyses showed an association of JSSc with the adult-onset SSc allele DRB1∗01, it was only in children with older onset (>11 years old) and with centromere antibody positivity. A novel association with DRB1∗10 was observed in childhood-onset SSc (odds ratio [OR] 7.48, P = 0.002), which remained significant regardless of JSSc subtype (limited or diffuse) or antibody positivity (topoisomerase, centromere antibody).

Numerous candidate genes outside of the HLA locus have been identified in adult-onset SSc, with important implications for prognosis and treatment. Only rare individual cases have been identified in pediatric-onset disease, which is likely to carry a larger genetic component. Whole exome sequencing identified a NOTCH4 variant in a case study of an 8-year-old girl with SSc manifesting with Raynaud phenomenon, digital tip ulcers, nailfold capillary changes, and skin thickening (diffuse cutaneous), who had a maternal grandfather and maternal aunt with SSc. The NOTCH4 coding variant may possibly explain some of the underlying vascular endothelial changes seen in the proband child with SSc.

Overview of Pathogenesis

SSc has traditionally been classified as an autoimmune disease with immune involvement demonstrated clinically by a distinct presentation of circulating disease-specific autoantibodies and predominate infiltrates and abnormalities of immune cells, including lymphocytes (T and B cells) and macrophages, in the skin and affected organs. ^, These immune cell alterations then contribute to an exaggerated and progressive fibrous collagen and extracellular molecule deposition, leading to fibroproliferative structural abnormalities in affected organ systems of SSc patients, ultimately leading to clinical symptoms of the disease. Endothelial and fibroblast dysfunction is apparent in the physical presentation of disease with endothelial abnormalities such as Raynaud phenomenon, capillary dropout, endothelial injury, and fibrosis as the result of increased synthesis and fibroblast-driven deposition of extracellular matrix proteins, hallmark features of SSc. These three relatively unassociated areas of abnormal function undergo several immunological alterations and communicate to propagate SSc disease ( Fig. 27.1 ). The majority of the understanding of these pathways has been extracted from the adult SSc literature.

Immunological Factors

SSc and associated fibrotic autoimmune diseases are thought to be propagated by improperly activated resident tissue macrophages that secrete chemokines to recruit T cells. The resulting imbalance of T cells further produces proinflammatory chemokines and cytokines that stimulate fibroblasts and other surrounding cells. ^, The mechanism behind macrophage activation and regulation of fibrogenesis by macrophages is unclear; however, the presence of both M1 and M2 macrophage phenotypes in the genome of SSc patients with fibrosis has been reported. The activation of these macrophages originates from many different pathways. Irregular signaling of the Wnt/β-catenin pathway, which results in profibrotic macrophage activation and lack of fibrotic regulation, has been shown in SSc patients. Dysregulation of the Janus kinase (Jak)–signal transducer and activator of transcription (STAT) signaling pathway has also been shown to contribute to fibrosing diseases such as SSc, with a recent case series reporting some effectiveness of a Jak inhibitor in decreasing skin thickness. Specifically in SSc, STAT receptors (STAT3 and STAT6) in fibroblasts have been shown to be dysregulated by cytokine induction and may be responsible for skewing SSc macrophages toward a profibrotic phenotype. Additionally, functional studies show that cadherins, specifically CDH11 , are responsible for the regulation of macrophages, fibroblast invasion, and adhesion between macrophages and myofibroblasts. ^,

Studies into the cellular and cytokine profiles of SSc tissue and peripheral blood suggest that a complex immune cascade causes a T-helper (Th)–related cellular infiltrate and plays a major role in disease initiation ( Fig. 27.1 ). In SSc, studies have indicated that the immune profile of early disease differs from that of late disease, with inflammation defining early disease and fibrosis defining later stages of disease. Mononuclear cell (MNC) infiltrates in early lesions, as well as altered function of Th and natural killer (NK) cells throughout the disease course, are thought to create a cytokine, chemokine, and growth factor profile that stimulates fibroblasts to promote fibrosis. MNC infiltration in various organ systems occurring in early disease consists of lymphocytes, plasma cells, and fibroblast-histiocytic cells around small blood vessels, eccrine sweat glands, and subcutaneous tissue. Notably, these findings are similar in LS, and tend to be difficult to distinguish by histopathology (see Chapter 28 ). The Th cell subsets and their associated cytokines have been shown to play a major role in this positive feedback loop of inflammation. ^{, , ,} Effector cells associated with Th cells include Th1, Th2, and Th17 cells. These differentiated cells are characterized by the cytokines they produce, interferon-γ (IFN-γ), interleukin-4 (IL-4)/IL-13, and IL-17, respectively.

Surface HLA class II molecules and the identification of CD4 ⁺ Th cell lineage and its effector cytokines in biopsies of skin lesions, ^{, ,} peripheral circulation (adult and pediatric), ^{, , ,} and culture in supernatants of peripheral blood mononuclear cells (PBMCs) of SSc patients indicate prominent active T-lymphocyte presence. These cells have been further characterized as CD4 and CD8 specific Th1 cells in the dermis of early SSc patients, ^, and IL-4 and IL-13 specific Th2 cells in conjunction with decreased Th17 cells in the peripheral blood and tissue of later SSc patients. ^{, ,}

Fibroblasts and Endothelium

It is thought that this environment of T-cell–associated chemokines and cytokines, initiated and contributed to by macrophages, stimulates fibroblasts and endothelial cells to produce fibrosis ( Fig. 27.1 ). Innate cells directly stimulate fibroblasts and can additionally contribute to activating endothelial cells of the vasculature and recruiting circulating cells to the tissue. Several growth factors have been identified in the skin of SSc patients that could induce fibrosis, such as transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), and adhesion molecules. TGF-β and CTGF stimulate tissue fibrosis (via increased collagen production) and endothelial cell damage (via influence of adhesion molecules intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1]). ^, These factors act primarily on fibroblasts and endothelial cells to synthesize extracellular matrix proteins including types I and III collagen and indirectly promote fibrosis by inhibiting collagenase activity.

One sequela of vascular dysregulation in SSc is pulmonary hypertension. In healthy individuals, nitric oxide (NO) acts as a signaling molecule on vascular smooth muscle cells to induce vasodilation by binding to soluble guanylate cyclase and mediates the synthesis of the secondary messenger cyclic guanosine monophosphate (cGMP). The synthesized cGMP acts as a secondary messenger and activates a cGMP-dependent protein kinase (protein kinase G) to regulate cytosolic calcium ion concentration. This changes the actin-myosin contractility, which results in vasodilation. NO also reduces pulmonary smooth muscle cell growth and antagonizes platelet inhibition, factors which play a key role in the pathogenesis of pulmonary arterial hypertension (PAH). NO is produced by the enzyme endothelial nitric oxide synthetase (eNOS). In patients with PAH, eNOS levels are reduced, resulting in overall lower levels of endothelial cell-derived NO and reduced vasodilation of smooth muscle cells.

In the skin, the expanding dermis replaces the subcutaneous adipose layer and displaces the dermal structures such as blood vessels, eccrine glands, and hair follicles. This causes many of the documented clinical presentations by limiting blood supply, which leads to progressive tissue hypoxia with induction of local production of vascular endothelial growth factor (VEGF) and other angiogenic factors.

Endothelial cell injury ( Fig. 27.1 ), resulting from either displacement or cytokine and chemokine production, is also thought to contribute to fibrosis and may be part of the initial inflammatory stage. Damage to the endothelial cells is evident in SSc through histological examination and increased levels of factor VIII–related antigens of SSc lesions. This results in increased vascular permeability, which is responsible for the edematous phase of the illness, leading to activation of fibroblasts, increased collagen production, and resultant fibrosis.

Once initiated, fibrosis is propagated through multiple feed-forward amplification loops that promote fibroblast activation and differentiation generated as a consequence of tissue damage, increased matrix stiffness, hypoxia, oxidative stress, and accumulation of damage-associated molecular patterns (DAMPs). Although TGF-β1 is known to initiate fibrosis, CTGF may play a greater role in maintaining and promoting fibrosis. Despite the increased numbers of collagen-producing fibroblasts in the skin, collagen production is similar to healthy fibroblasts. However, biochemical analysis indicates excessive deposition of the fibrillar collagens (type I and type III), type V and type VII collagens and elastin fibrils, and elevated levels of enzymes that catalyze posttranslational collagen modifications, such as lysyl hydroxylase and lysyl oxidase, in SSc. ^, Scleroderma mouse models have shown that lysophosphatidic acid and its receptor, LPA1, are important for dermal fibrosis through enhanced migration.

Understanding the process of fibroblast recruitment, activation, and additional activation or differentiation into myofibroblasts adds another layer of complexity that is still relatively unexplored ( Fig. 27.1 ). Myofibroblasts are thought to play a key role in tissue fibrosis in SSc and can originate from many different sources. These cells are generally characterized by a profibrotic phenotype causing an increased production of fibrillar type I and type III collagens, expression of α-smooth muscle actin (α-SMA), and reduction of extracellular matrix protein (ECM)-degradative enzymes. Additionally, myofibroblasts mechanically stimulate tissue by producing contractile forces that allow the cells to migrate and inadvertently causes an increase in mechanical tissue stiffness. The source of myofibroblasts is diverse and has been attributed to the differentiation of quiescent resident tissue fibroblasts, bone marrow-derived circulating CD34 ⁺ fibrocytes, epithelial cells, adipocytes, perivascular cells (pericytes), ^, and endothelial cells (ECs) that have acquired a mesenchymal phenotype. This EC/mesenchymal acquisition process is called endothelial-to-mesenchymal transition (EndoMT), where affected cells lose their specific cell-defining markers and initiate the expression of mesenchymal cell markers including α-SMA, vimentin, and type I collagen. ^, Endothelial cells from patients with SSc have been found in various stages of this transition process, coexpressing myofibroblast-specific markers with native cell markers in the lungs, kidneys, and veins. ^,

Yet another layer of complexity is introduced by adipose tissue, which is important because the dermis is in direct contact with the subcutis, and histologically the deep (reticular) dermis and subcutis are most affected in scleroderma for both the inflammatory and fibrotic components. Adipocytes release adipokines that are metabolically active and classified based on their mechanism of action: auto-, para-, or endocrine hormones, and adipokines heavily influence immune response. Many of these factors have been demonstrated to be different (higher or lower) in patients with SSc compared with controls in various studies and include adiponectin, resistin, leptin, visfatin, chemerin, and vaspin, in addition to cytokines (IL-6, TNF-α), coagulation factors (PAI-1), growth factors (VEGF, TGF-β), or complement system proteins (adipsin). In SSc skin and blood, adiponectin, vaspin, apelin, and omentin were found to be decreased in patients with SSc and correlated to skin scores such as the modified Rodnan skin score (mRSS) and clinical presentation such as pulmonary abnormalities. ^, Resistin, visfatin, and adipsin were found to be increased in SSc patients correlating with renal and pulmonary factors, as well as common antibody levels such as anti–Scl-70 and anticentromere antibodies. Other evaluated factors, such as leptin and chemerin, have had mixed results with both increases and decreases in adipokine levels correlating with various disease measures such as arterial stiffness and disease duration. ^, These factors could potentially initiate or propagate SSc through immune activation as adipocytes are commonly one of the first cell types activated and then depleted in scleroderma skin (resulting clinically in subcutaneous atrophy). For example, proinflammatory adipokines such as leptin, resistin, and adipsin increase inflammatory chemokine and cytokine environments and decrease immune regulatory functions. ^, Furthermore, adipocytes can differentiate into myofibroblasts, which have been shown to be key to SSc fibrosis via the adipocyte–myofibroblast transition (AMT). Similar to EndoMT transition, adipose cells acquire mesenchymal features, lose intercellular contact, and gain the ability to migrate. This suggests that SSc adipocyte loss could be caused by cellular differentiation instead of fibrotic displacement and could implicate a larger role for adipocytes in the pathogenesis of disease. ^, Limited studies into adipogenesis have indicated that SSc adipose-derived stem cells have limited proliferation and migration capabilities but maintain the ability to expand and differentiate into cells with a myofibroblast-like phenotype.

Cutaneous

Cutaneous manifestations frequently bring children to medical attention, but because of the insidious and subtle onset of skin changes, there is often a delay in diagnosis with a mean time of 1.9 and 2.8 years between first sign of disease and diagnosis. ^, In general, in SSc, the skin transitions through three phases: edematous, sclerosis (or induration), and atrophy. Skin involvement occurs in nearly all JSSc patients with the exception of the few rare “systemic sclerosis sine scleroderma” patients, in which the patient has RP and severe internal organ manifestation typical for SSc but no skin thickness. In children, only a handful of case reports include this phenotype. In adult cohorts, SSc sine scleroderma occurs in low frequency, approximately 5% to 9% of larger cohorts, and typically manifests with RP, digital tip ulcers, telangiectasia, and SSc-specific autoantibodies in context to significant organ manifestation, such as ILD.

Edematous Phase

Early in the clinical course, the skin and underlying subcutis are edematous, with particular predilection for the distal extremities, appearing as puffy fingers and hands or swollen feet and ankles ( Fig. 27.3 ); less commonly, the more proximal limb, face, and trunk are edematous.

Sclerosis Phase

The sclerosis phase, for which scleroderma is named, typically follows after several weeks to months and is characterized by loss of the natural pliability of the skin and the presence of a palpable skin thickness. The skin takes on a shiny, tense appearance becoming tight, hard, and more bound down to the subcutaneous tissue, most apparent in the hands as sclerodactyly ( Fig. 27.4 ). The fibrotic phase is particularly noticeable on the dorsum of fingers and hands, termed acrosclerosis , causing tacked-down distal tapering of the fingers ( Fig. 27.5 ). Over time, as skin thickens and underlying structures, such as tendons, become affected and shortened, the finger joints start to lose range of motion both in extension and flexion ( Fig. 27.5 ), and in more severe cases, a “claw hand” deformity results, with great impact on performing activities of daily living. The typical scleroderma facies from sclerotic skin changes is characterized by a pinched nose, thin pursed lips, small mouth with diminished oral aperture, prominent teeth ( Fig. 27.6 ), and an expressionless appearance. The degree of skin thickness throughout the body is a surrogate measure of total disease severity in SSc. Skin thickness is measured as none-mild-moderate-severe (graded 0 to 3) throughout 17 areas of the body and a cumulative score is obtained using the mRSS ( Fig. 27.7 ). The mRSS is obtained over longitudinal visits and a skin thickness progression rate (STPR) can be calculated and assist in predicting timing of internal organ involvement in those with dcSSc. A high STPR is associated with scleroderma renal crisis in patients with adult SSc, whereas an improving skin score signifies stable disease status and survival improvement. Further study is being conducted in JSSc to assess the correlation of the mRSS with disease severity and prognosis in children. Initial studies did propose mindfulness of degree of skin pliability in a developing child, with younger healthy children having more adherent skin to the subcutis, potentially being scored as mild skin thickness. A few JSSc cohorts have determined the average mRSS in children and in general, it is slightly lower than reported mean mRSS in adult cohorts ( Table 27.5 ).

Atrophy

Atrophy of the skin develops in the final phase, in which the initial edematous and fibrotic areas become atrophic, with thin skin and subcutis, visible veins (making the skin look gray or blue), and predominant postinflammatory hyper- and hypo-pigmentation. Hyperpigmentation is especially noticeable around the neck; areas of folding/friction such as axilla, antecubital fossa, and popliteal fossa; and the trunk, specifically around the waistline.

Other features characteristic of SSc include telangiectasias, calcinosis, digital pitting, and ulceration (the latter described in the section Raynaud Phenomenon). Telangiectasias of scleroderma skin and mucosal membranes are not like spider angiomas with a central vessel and wheel-like appearance, but they more typically have a matted appearance under microscopy/dermatoscope, with occurrence most prominent on the face and upper extremities ( Fig. 27.8 ). Calcinosis of the subcutis layer in JSSc occurs in a similar manner to dermatomyositis, with areas of friction most frequently involved, with an area of hard calcium developing into a nodule type of lesion that can ulcerate and extrude calcium ( Fig. 27.9 ). Involvement of the extensor surface of the MCPs is quite common, as well as that of the elbow. As in dermatomyositis, calcinosis is thought to be a combination of disease severity and chronic active disease.

Vascular

Alongside cutaneous features, certain vascular features are hallmarks of SSc, typically exhibited at the onset of disease and eventually present in nearly all JSSc patients. Common features at the onset of JSSc are RP (70%) and skin changes of the hands (60%), including edema, sclerodactyly, and induration proximal to the MCPs. In the largest cohort of pediatric patients with SSc studied (153 patients), 53% presented with both skin induration of the hands and RP, and 10% of those presenting with RP also had digital infarcts. Throughout the course of the disease, almost all will have RP (97%) and skin changes of the hands (96%), and digital ulcers will develop in up to a half of patients ( Table 27.5 ). ^{, , , , ,} RP results from transient vasospasm and vasoconstriction of the arterioles, causing color change of pallor from transient ischemia with pain, numbness, and tingling, then cyanosis from deoxygenation, with an erythematous phase upon rewarming ( Fig. 27.10 ). In SSc, RP is considered secondary resulting from the underlying connective disease, with the additional issue of vasculopathy causing a stiffer vessel and unhealthy, thickened endothelium. RP in this instance leads to episodes of recurrent and prolonged ischemia, which in turn cause digital pitting and ulcers at the pulp of the fingertips and, in extreme cases, gangrene of the finger ( Fig. 27.11 ).

The vasculopathy in SSc can be further demonstrated by visualizing the NFC with a dermatoscope, ophthalmoscope at 40+ diopters, or nailfold microscopy. Instead of uniform thin “picket fence” pattern, the NFC are often dilated (>2 times the normal width) and tortuous, demonstrating areas of hemorrhage, telangiectasia, and later, dropout (absence of NFC) and arborization of the capillaries ( Fig. 27.12 ). These changes are observed in juvenile and adult SSc, and, if identified in the context of RP, should strongly raise suspicion for diagnosis of JSSc. ^, The prevalence of NFC changes in JSSc is reported to be 50%, ^{, , ,} but is likely higher if standardized microscopy is performed. Abnormal perfusion to the fingers is believed to contribute to cuticular hypertrophy and dystrophic nails, in addition to tapering of the fingertips, resorption of the distal phalanges (acroosteolysis) ( Fig. 27.13 ), and shortening of the middle and distal phalanges, the latter seen in adults who have had childhood-onset SSc.

Musculoskeletal

Compared with adult-onset SSc, musculoskeletal involvement is more common in JSSc. Approximately one-third of patients with JSSc experience joint effusions in addition to the typical dry synovitis of scleroderma, reflected by the fibrosis of tendons traversing the joints, which limits their range of motion (ROM). ^, Early in the disease process, especially in those with dcSSc, tenosynovitis/bursitis causes palpable tendon friction rubs (a “leathery crepitus”) when the joint is extended or flexed, ^, demonstrated in approximately 10% of patients with JSSc. ^, Tendon friction rubs in adult-onset SSc have been associated with early renal crisis, cardiac and GI complications, and poorer 5- and 10-year survival rates. Later in the disease, the initial skin, subcutis, and underlying connective tissue sclerosis cause joint contractures with limited ROM in large, medium, and small joints ( Fig. 27.5 ), most notably in the fingers and wrists, with resultant claw hand deformity in more severe cases.

A relatively brief assessment of the composite ROM impact is the finger-to-palm (FTP) measurement. This is measured with a measuring tape ruler from the distal palmar crease at the base of the middle finger to the tip of the pulp of the third finger while the 3rd finger is in full flexion in centimeters ( Fig. 27.14 ). A measurement of 0 is considered normal (able to touch fingertip to palmar crease). The inability to touch the distal fingertip to the palm in 1-cm increments reflects the general severity of disease, as a component of the Medsger severity scale. Further, measuring the difference of this measurement in full extension minus full flexion will provide a more solid composite score, termed delta FTP , which one can monitor over time.

Myopathy typically results in symmetrical proximal weakness and muscular atrophy. Muscle weakness has been reported to range between 20% and 32% in JSSc cohorts (see Table 27.5 ), ^{, , , , ,} and was markedly higher than the adult comparison cohort in one of the studies. Myositis also occurs, more commonly in the overlap SSc subtype, and presents similarly to juvenile dermatomyositis (JDM), but in a more “bland” fashion, with less elevation of muscle enzymes and less intense signal on magnetic resonance imaging (MRI) short tau inversion recovery (STIR) sequence of the muscle. Fasciitis might be demonstrated more than myositis, as seen in JLS. The muscle biopsy of SSc differs from that of JDM by having more fibrosis and the presence of thickened capillaries. Children with dcSSc and myositis are particularly at risk for severe cardiac involvement, including myocardial perfusion deficits and dilated cardiomyopathy.

Gastrointestinal

The tract is affected in 42% to 74% of children with SSc and may precede skin involvement. Although frequently asymptomatic, GI manifestations have been associated with ILD, malnutrition, and poor quality of life. ^{, , , ,} Vasculopathy and inflammation leading to fibrosis can manifest in the entire GI tract, from mouth to anus.

Gastrointestinal Assessments Recommended

A detailed history can identify GI manifestations if direct questions are asked, as patients may not feel comfortable mentioning bowel symptoms or may not know that they are pertinent to SSc. An assessment tool has been developed for adult-onset SSc, ^, which has yet to be validated in pediatric populations but can nonetheless serve as a resource for questions with high specificity and sensitivity. Some symptoms that patients may recognize are listed in Table 27.6 , but patients may be asymptomatic. Physical exam and imaging studies remain the gold standard for screening and monitoring anatomy and function in all children diagnosed with SSc. Dental exams are essential for detecting oral complications early and maintenance of dental hygiene.

TABLE 27.6

Symptoms Associated with Gastrointestinal Systemic Sclerosis

Level	Symptoms
Mouth	Xerostomia, food stuck in neck, coughing while eating, dysphonia
Esophagus	Morning hoarseness, heartburn, night cough
Stomach	Anorexia, early satiety, halitosis, bloating, nausea, vomiting, heartburn
Small Intestines	Distention, abdominal pain, weight loss, steatorrhea, diarrhea, obstipation
Colon Rectum Anus	Fecal incontinence, constipation, diarrhea, rectal prolapse, perforation

Radiological studies are directed by the symptoms of individual patients, but all patients should have an initial esophagram/UGI study with small bowel follow-through. A swallow study with speech pathology ascertaining the risk of aspiration is also typically recommended. Videofluoroscopy, if available, during barium swallow study can detect pharyngeal muscle weakness. Children with abnormal esophageal anatomy on UGI have been shown to have a larger mean esophageal diameter on high-resolution computed tomography (HRCT) scan, as well as ILD, a finding also reported in adult patients. ^{, ,} Thus, esophageal findings on UGI or HRCT, despite lack of symptoms, should raise concern for esophageal dysfunction and prompt heightened surveillance for ILD. In addition to structural abnormalities, fluoroscopic UGI is used to evaluate abnormalities in esophageal function as depicted by abnormal or delayed peristalsis and/or bolus clearance ( Fig. 27.15 ). More dedicated testing for gastroesophageal reflux includes a 24-hour intraesophageal pH monitoring study, which provides more sensitivity and detail, such as number of silent reflux episodes, at what levels acid reflux occurs, and times of reflux in relation to body posture and eating. If abnormal peristalsis of the esophagus is detected, further evaluation with esophageal manometry is recommended because it is more sensitive and can provide more detailed information, such as lower esophageal pressure.

In the stomach , gastric emptying scintigraphy and fructose breath tests can be informative, and often endoscopy is indicated to assess for GAVE and gastritis, as well as esophagitis, in the case of anemia. Small intestinal function can be evaluated by the hydrogen breath test, fructose tolerance test, or capsule endoscopy. A barium enema can show dilatation of the colon, and rectal manometry can show a diminished rectoanal inhibitory reflex. A Sitz marker study, in which the patient ingests capsules containing radiopaque markers that are detected by a series of radiographs, can be used to calculate colonic transit time. Anorectal manometry is used to assess anal sphincter function whereas pelvic MRI and anal sonography are used to assess anal anatomy.