Categorization: Clinical and Serologic

SSc is a rare but potentially life-threatening condition. There are 3 main clinical subtypes associated with different morbidities (see Fig. 1 ): diffuse cutaneous (dc) SSc, characterized by widespread and rapidly progressive skin thickening (spreading proximal to elbows and knees) associated with early visceral disease (lung, heart, and kidney), limited cutaneous SSc (lcSSc), characterized by restricted and nonprogressive skin thickening (limited to distal extremities) associated with late visceral disease (pulmonary arterial hypertension, malabsorption), and overlap SSc, which can be dcSSc or lcSSc with features of another connective tissue disease, such as dermatomyositis or systemic lupus erythematosus (SLE). Patients with CREST syndrome (calcinosis, Raynaud phenomenon (RP), esophageal dysmotility, sclerodactyly, and telangiectasia) are considered to have lcSSc. Some patients with undifferentiated or mixed connective tissue disease may have shiny or full-appearing skin of the distal fingers, but they must have the major criterion, namely skin induration or sclerosis proximal to the metacarpal phalangeal (MCP) or metatarsophalangeal (MTP) joints, to be considered to have juvenile SSc ( Fig. 2 ). There are an additional 2 minor criteria required for the diagnosis of SSc in children according to international consensus agreement ( Box 1 ). In addition to the extent of skin thickening, particular scleroderma-related serum autoantibody profiles assist in identifying subsets of SSc and predicting their organ involvement in both adult-onset and childhood-onset SSc. For example, antitopoisomerase antibody (Scl-70) would be expected in a patient with dcSSc, and would be worrisome for a rapid skin progression and the development of interstitial lung disease (ILD). The 4 most common antibodies in pediatric SSc are antitopoisomerase antibody (Scl-70) (20%–34%), typically associated with dcSSc and ILD as mentioned, followed by anticentromere antibody (ACA) (2%–16%), associated with lcSSc and pulmonary arterial hypertension (PAH), and antiU1-RNP and Pm-Scl (polymyositis-scleroderma) antibodies (2%–16%), both of which are commonly found in those with overlap syndromes of SSc and other connective tissue diseases with more prominent arthritis and myositis features, such as dermatomyositis or SLE. The U1-RNP and Pm-Scl positive proportion of patients is likely higher than reported because some investigators do not include cases of overlap SSc or mixed connective tissue disease in their pediatric SSc cohorts. Overall, the frequency of these antibodies in children reflects the clinical subset frequencies of dcSSc, lcSSc, and overlap SSc Compared with adult SSc, overlap SSc is much more common in pediatric SSc (29% vs 9%), as reflected by the increased frequency of U1-RNP and Pm-Scl antibodies, and is related to the higher percentage of myositis and arthritis observed in pediatric SSc. There are several other SSc-related autoantibodies that associate with different organ manifestations; however, they are much less common in childhood-onset SSc. One of these is RNA polymerase III (POL3) antibody, which relates to severe renal disease in the form of scleroderma renal crisis. POL3 is rarely observed in childhood-onset SSc, but can be found in up to 30% of adult-onset SSc patients and reflects the clinically significant higher proportion of renal disease in adult SSc. Although many scleroderma-related autoantibodies have been identified in adult SSc, there is a high proportion of pediatric patients (20%–23%) who have a positive antinuclear antibody (ANA) test without a specific autoantibody identified.

Typical shiny and thick skin of the hands with skin induration traveling up the forearm (past the metacarpal phalangeal joints) in a patient with systemic sclerosis.

Clinical Manifestations

Common features at the onset of pediatric SSc are raynaud phenomenon (RP) (70%) and skin changes of hands (60%) including edema, sclerodactyly, and induration proximal to the MCPs. In the largest cohort of pediatric SSc (153 patients) studied, 53% presented with both skin induration of hands and RP, and 10% of those presenting with RP also had digital infarcts ( Fig. 3 ). Throughout the course of the disease, almost all will have RP (97%) and skin changes of the hands (96%).

A teenage girl with typical ( A ) sclerodactyly and ( B ) digital pitting and ulcers.

RP is a vasospastic response leading to a triphasic color change of the hands (first pallor because of vasoconstriction, then blue secondary to cyanosis, and finally red because of reperfusion with subsequent swelling and pain) associated with a sensation of numbness and tingling. RP can also occur in toes and other acral areas including the ears, tip of the nose, or tongue. In SSc, arterioles are more narrow and stiff because of marked intimal hyperplasia and fibrosis from endothelial dysfunction, which leads to more pronounced RP with resultant tissue damage/ischemia. These vasculopathic changes are identifiable in the nailfold capillary beds of these patients by capillary microscopy, demonstrating dilatation, tortuosity, hemorrhage, drop-off (avascularization), and later arborization of the capillaries. The prevalence of nailfold capillary changes in pediatric SSc is reported to be 50%, but is likely higher if standardized microscopy is performed. Poor perfusion of the fingers eventually leads to digital-tip pitting, ulceration (see Fig. 3 B), and in more severe cases autoamputation. Healthy individuals can also experience RP without being at risk for developing an underlying connective tissue disease (primary RP). These individuals typically never develop digital-tip ulcers or have nailfold capillary changes because they do not have an underlying vasculopathy. Features that help the clinician differentiate primary RP from that secondary to a connective tissue disease in both children and adults are the following: lack of nailfold capillary changes, digital-tip pitting and/or ulceration, and a negative ANA.

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. Early in the clinical course, the skin is edematous with particular predilection for the distal extremities; rarely, involvement of the more proximal limb, face, and trunk is present. The induration phase, for which scleroderma is named, 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 with distal tapering of the fingers (see Figs. 2 and 3 A). Over time as skin thickens and underlying structures, such as tendons, become affected and shortened, the finger joints start to lose range of motion in both extension and flexion, and in more severe cases a claw-hand deformity results, with great impact on performing activities of daily living. The typical scleroderma facies of tight skin and skin atrophy produces a pinched nose, thin pursed lips, small mouth, prominent teeth, and an expressionless appearance ( Fig. 4 ). Skin thickness is measured as mild, moderate, and severe throughout the body, and a cumulative score is obtained using the modified Rodnan skin score (mRSS). 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.

Expressionless facies of scleroderma in a prepubertal girl with decreased oral aperture and pursed lips.

Other skin findings in SSc include subcutaneous calcium deposits (calcinosis cutis), which may occur at pressure points, typically found on extensor surfaces of hand joints in SSc, and may occasionally extrude through the skin in a fashion similar to dermatomyositis. These lesions may be painful and may ulcerate. However, they are more typically associated with chronic disease and are rarely present at the time of disease onset and diagnosis. Telangiectasias are also a manifestation of SSc, most typically found in the lcSSc variant (previously known as CREST syndrome), and are commonly distributed on the face and upper extremities.

Other organ manifestations in SSc (in order of decreasing frequency) include gastrointestinal, pulmonary, musculoskeletal, cardiac, renal, and neurologic symptoms. Gastrointestinal symptoms occur in approximately half of the children, although more detailed investigation often indicates the presence of abnormalities in a larger percentage. Esophageal dysmotility and gastroesophageal reflux often leads to dysphagia and esophagitis. Distal dysphagia, especially with solids, causing a sensation of food getting stuck mid-chest, is typical and represents dysfunction of the distal smooth muscle of the esophagus. Gastroparesis with delayed gastric emptying in addition to esophageal dysfunction can lead to increased reflux symptoms. Typically patients will complain of nighttime cough when lying prone, owing to silent aspiration, and a brackish taste in their mouth on wakening, due to silent reflux. Chronic reflux may lead to esophageal strictures. Evaluation of the gastrointestinal (GI) tract using manometry and intraesophageal 24-hour pH monitoring have been reported as sensitive indicators of lowered esophageal tone and reflux. However, these modalities are used less often in pediatrics. Instead, a swallow study to evaluate for aspiration and dysmotility, followed by an upper GI study with small bowel follow-through, is typically used. If the small bowel is involved, cramps, diarrhea, and constipation may result from peristaltic dysfunction. Episodes of pseudo-obstruction with postprandial abdominal distension, pain, and nausea can occur because of a functional ileus. Bacterial overgrowth, steatorrhea, weight loss, volvulus, and even perforation can occur. Colonic disease occurs in the form of wide-mouth diverticula and a loss of the normal colonic architecture. Another complication of GI involvement with SSc is acute GI bleeding associated with gastric antral venular ectasia (GAVE) requiring photocoagulation. This condition is uncommon in children and is associated with early dcSSc, RNA polymerase III–positive patients.

Pulmonary involvement in pediatric SSc ranges from 30% to 70% in the literature, and includes ILD, PAH (either primary, which results from vasculopathy, or secondary from ILD), and abnormal pulmonary function tests (PFTs). PFT abnormalities of special of concern are decreased forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO). ILD typically begins with an inflammatory phase, alveolitis, characterized by a mixed cellular infiltrate in the lung interstitium that spills over into the alveolar spaces. Bronchoalveolar lavage (BAL) demonstrates increased neutrophils and/or eosinophils in addition to alveolar macrophages. The presence of alveolitis is also suggested by ground-glass opacities on high-resolution computed tomography (HRCT) scans of the lungs. As ILD progresses, inflammation subsides, as there is a transition toward fibrosis with the thickening of alveolar walls and remodeling of the lung. Progressive pulmonary fibrosis may result in moderate to severe restrictive lung disease with significant decrease in FVC and DLCO. Clinically, ILD typically presents as slowly progressive dyspnea with exertion over years. In comparison, PAH presents with rapid progression of dyspnea on exertion over months. In the setting of PAH, PFTs demonstrate a decreased DLCO and abnormal echocardiogram findings with estimated pulmonary artery (PA) or right ventricular (RV) systolic pressure of greater than 40 mm Hg, verified by right-heart catheterization with mean PA pressure greater than 25 mm Hg. For most children with SSc or suspected SSc, initial assessment includes chest radiograph, PFTs, including DLCO, and an echocardiogram. Additional cardiopulmonary testing is pursued if abnormalities are detected or the patient is too young to appropriately complete testing (ie, PFTs). Abnormal PFTs prompt evaluation with HRCT of chest, and possibly BAL, if further evidence of inflammation (alveolitis) is required or evaluation of infection is needed before starting therapy. Evidence of PAH on echocardiogram is more formally assessed by right-heart catheterization.

Compared with adult-onset SSc, musculoskeletal involvement is more common in pediatric SSc. Approximately 30% to 40% of those with pediatric SSc experience inflammatory arthritis (joint effusions) in addition to the typical dry synovitis of scleroderma, reflected by the fibrosis of tendons transversing the joints, which limits their range of motion. 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. When the patient has myopathy, typically there is a symmetric proximal weakness, especially of the shoulder girdle and humeral muscles, sometimes with pronounced atrophy. Myositis is also reflected by elevated muscle enzymes and changes on magnetic resonance imaging (MRI) of muscle groups similar to those of juvenile dermatomyositis (JDM). 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.

Cardiac involvement, although infrequent, is the major cause of scleroderma-related mortality in children with SSc, and is evidenced by 10 of 15 deaths in Martini and colleagues’ cohort and 5 of 32 deaths in Scalapino and colleagues’ cohort. Cardiac manifestations result from the combination of myocardial fibrosis, vascular insufficiency, and inflammation, and include heart block, arrhythmia, congestive heart failure, cardiomyopathy, and pericarditis. In contrast to pediatric SSc, scleroderma-related mortality in adults is primarily caused by pulmonary involvement, both ILD and PAH.

Mild renal dysfunction is not uncommon in SSc and is secondary to vasculopathy instead of glomerulonephritis, which is observed in SLE. This consideration is supported by pathologic findings of intimal proliferation of the interlobular arteries of the kidney and lack of active urinary sediment (ie, red blood cell casts). By contrast, a more severe and morbid form of renal disease, scleroderma renal crisis (SRC), occurs only in approximately 15% of adult patients with SSc and is even less common in children. SRC is characterized by accelerated arterial hypertension, renal insufficiency, microangiopathic hemolytic anemia, and thrombocytopenia. In adult SSc, SRC previously had a 20% survival rate at 1 year, but now has an 80% survival rate owing to the advent of angiotensin-converting enzyme inhibitors. SRC is most frequently seen early in the disease course of dcSSc RNA-polymerase III–positive patients and is thought to be augmented by higher doses of corticosteroids. Renal crisis is rare in children with SSc, with fewer than 5% affected and only 5 cases reported (2 of whom died of renal disease) among the 3 large published cohorts.

Outcome

Despite the potential organ involvement in pediatric SSc, it has a far more favorable prognosis at 5, 10, and 15 years compared with adult SSc, with a lower frequency of severe organ involvement. Foeldvari and colleagues recently reported Kaplan-Meier survival rates at 10 years for children to be 98% versus 75% in adults. Treatment of SSc is dependent on organ involvement, but general measures such as antacid medication for GI protection, prokinetic agents for dysmotility, rotating antibiotics for malabsorption, as well as vasodilators for RP (may also help with PAH), and nonsteroidal anti-inflammatory drugs and physical therapy for arthritis or tendonitis are generally recommended. Corticosteroids for myositis, arthritis, and other inflammatory clinical features must be used with caution, as they can prompt SRC. More specific treatment recommendations for different organ manifestations have been agreed on by a consensus conference of international scleroderma experts, and were published in 2009. It is notable that in the treatment of both pediatric and adult SSc early diffuse skin disease, there has been a shift from the use of d -penicillamine to mycophenolate mofetil (MMF) likely because of its potential antiproliferative effects, although it is not included in the treatment recommendations previously discussed.

Categorization: Clinical and Serologic

SSc is a rare but potentially life-threatening condition. There are 3 main clinical subtypes associated with different morbidities (see Fig. 1 ): diffuse cutaneous (dc) SSc, characterized by widespread and rapidly progressive skin thickening (spreading proximal to elbows and knees) associated with early visceral disease (lung, heart, and kidney), limited cutaneous SSc (lcSSc), characterized by restricted and nonprogressive skin thickening (limited to distal extremities) associated with late visceral disease (pulmonary arterial hypertension, malabsorption), and overlap SSc, which can be dcSSc or lcSSc with features of another connective tissue disease, such as dermatomyositis or systemic lupus erythematosus (SLE). Patients with CREST syndrome (calcinosis, Raynaud phenomenon (RP), esophageal dysmotility, sclerodactyly, and telangiectasia) are considered to have lcSSc. Some patients with undifferentiated or mixed connective tissue disease may have shiny or full-appearing skin of the distal fingers, but they must have the major criterion, namely skin induration or sclerosis proximal to the metacarpal phalangeal (MCP) or metatarsophalangeal (MTP) joints, to be considered to have juvenile SSc ( Fig. 2 ). There are an additional 2 minor criteria required for the diagnosis of SSc in children according to international consensus agreement ( Box 1 ). In addition to the extent of skin thickening, particular scleroderma-related serum autoantibody profiles assist in identifying subsets of SSc and predicting their organ involvement in both adult-onset and childhood-onset SSc. For example, antitopoisomerase antibody (Scl-70) would be expected in a patient with dcSSc, and would be worrisome for a rapid skin progression and the development of interstitial lung disease (ILD). The 4 most common antibodies in pediatric SSc are antitopoisomerase antibody (Scl-70) (20%–34%), typically associated with dcSSc and ILD as mentioned, followed by anticentromere antibody (ACA) (2%–16%), associated with lcSSc and pulmonary arterial hypertension (PAH), and antiU1-RNP and Pm-Scl (polymyositis-scleroderma) antibodies (2%–16%), both of which are commonly found in those with overlap syndromes of SSc and other connective tissue diseases with more prominent arthritis and myositis features, such as dermatomyositis or SLE. The U1-RNP and Pm-Scl positive proportion of patients is likely higher than reported because some investigators do not include cases of overlap SSc or mixed connective tissue disease in their pediatric SSc cohorts. Overall, the frequency of these antibodies in children reflects the clinical subset frequencies of dcSSc, lcSSc, and overlap SSc Compared with adult SSc, overlap SSc is much more common in pediatric SSc (29% vs 9%), as reflected by the increased frequency of U1-RNP and Pm-Scl antibodies, and is related to the higher percentage of myositis and arthritis observed in pediatric SSc. There are several other SSc-related autoantibodies that associate with different organ manifestations; however, they are much less common in childhood-onset SSc. One of these is RNA polymerase III (POL3) antibody, which relates to severe renal disease in the form of scleroderma renal crisis. POL3 is rarely observed in childhood-onset SSc, but can be found in up to 30% of adult-onset SSc patients and reflects the clinically significant higher proportion of renal disease in adult SSc. Although many scleroderma-related autoantibodies have been identified in adult SSc, there is a high proportion of pediatric patients (20%–23%) who have a positive antinuclear antibody (ANA) test without a specific autoantibody identified.

Typical shiny and thick skin of the hands with skin induration traveling up the forearm (past the metacarpal phalangeal joints) in a patient with systemic sclerosis.

Clinical Manifestations

Common features at the onset of pediatric SSc are raynaud phenomenon (RP) (70%) and skin changes of hands (60%) including edema, sclerodactyly, and induration proximal to the MCPs. In the largest cohort of pediatric SSc (153 patients) studied, 53% presented with both skin induration of hands and RP, and 10% of those presenting with RP also had digital infarcts ( Fig. 3 ). Throughout the course of the disease, almost all will have RP (97%) and skin changes of the hands (96%).

A teenage girl with typical ( A ) sclerodactyly and ( B ) digital pitting and ulcers.

RP is a vasospastic response leading to a triphasic color change of the hands (first pallor because of vasoconstriction, then blue secondary to cyanosis, and finally red because of reperfusion with subsequent swelling and pain) associated with a sensation of numbness and tingling. RP can also occur in toes and other acral areas including the ears, tip of the nose, or tongue. In SSc, arterioles are more narrow and stiff because of marked intimal hyperplasia and fibrosis from endothelial dysfunction, which leads to more pronounced RP with resultant tissue damage/ischemia. These vasculopathic changes are identifiable in the nailfold capillary beds of these patients by capillary microscopy, demonstrating dilatation, tortuosity, hemorrhage, drop-off (avascularization), and later arborization of the capillaries. The prevalence of nailfold capillary changes in pediatric SSc is reported to be 50%, but is likely higher if standardized microscopy is performed. Poor perfusion of the fingers eventually leads to digital-tip pitting, ulceration (see Fig. 3 B), and in more severe cases autoamputation. Healthy individuals can also experience RP without being at risk for developing an underlying connective tissue disease (primary RP). These individuals typically never develop digital-tip ulcers or have nailfold capillary changes because they do not have an underlying vasculopathy. Features that help the clinician differentiate primary RP from that secondary to a connective tissue disease in both children and adults are the following: lack of nailfold capillary changes, digital-tip pitting and/or ulceration, and a negative ANA.

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. Early in the clinical course, the skin is edematous with particular predilection for the distal extremities; rarely, involvement of the more proximal limb, face, and trunk is present. The induration phase, for which scleroderma is named, 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 with distal tapering of the fingers (see Figs. 2 and 3 A). Over time as skin thickens and underlying structures, such as tendons, become affected and shortened, the finger joints start to lose range of motion in both extension and flexion, and in more severe cases a claw-hand deformity results, with great impact on performing activities of daily living. The typical scleroderma facies of tight skin and skin atrophy produces a pinched nose, thin pursed lips, small mouth, prominent teeth, and an expressionless appearance ( Fig. 4 ). Skin thickness is measured as mild, moderate, and severe throughout the body, and a cumulative score is obtained using the modified Rodnan skin score (mRSS). 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.

Expressionless facies of scleroderma in a prepubertal girl with decreased oral aperture and pursed lips.

Other skin findings in SSc include subcutaneous calcium deposits (calcinosis cutis), which may occur at pressure points, typically found on extensor surfaces of hand joints in SSc, and may occasionally extrude through the skin in a fashion similar to dermatomyositis. These lesions may be painful and may ulcerate. However, they are more typically associated with chronic disease and are rarely present at the time of disease onset and diagnosis. Telangiectasias are also a manifestation of SSc, most typically found in the lcSSc variant (previously known as CREST syndrome), and are commonly distributed on the face and upper extremities.

Other organ manifestations in SSc (in order of decreasing frequency) include gastrointestinal, pulmonary, musculoskeletal, cardiac, renal, and neurologic symptoms. Gastrointestinal symptoms occur in approximately half of the children, although more detailed investigation often indicates the presence of abnormalities in a larger percentage. Esophageal dysmotility and gastroesophageal reflux often leads to dysphagia and esophagitis. Distal dysphagia, especially with solids, causing a sensation of food getting stuck mid-chest, is typical and represents dysfunction of the distal smooth muscle of the esophagus. Gastroparesis with delayed gastric emptying in addition to esophageal dysfunction can lead to increased reflux symptoms. Typically patients will complain of nighttime cough when lying prone, owing to silent aspiration, and a brackish taste in their mouth on wakening, due to silent reflux. Chronic reflux may lead to esophageal strictures. Evaluation of the gastrointestinal (GI) tract using manometry and intraesophageal 24-hour pH monitoring have been reported as sensitive indicators of lowered esophageal tone and reflux. However, these modalities are used less often in pediatrics. Instead, a swallow study to evaluate for aspiration and dysmotility, followed by an upper GI study with small bowel follow-through, is typically used. If the small bowel is involved, cramps, diarrhea, and constipation may result from peristaltic dysfunction. Episodes of pseudo-obstruction with postprandial abdominal distension, pain, and nausea can occur because of a functional ileus. Bacterial overgrowth, steatorrhea, weight loss, volvulus, and even perforation can occur. Colonic disease occurs in the form of wide-mouth diverticula and a loss of the normal colonic architecture. Another complication of GI involvement with SSc is acute GI bleeding associated with gastric antral venular ectasia (GAVE) requiring photocoagulation. This condition is uncommon in children and is associated with early dcSSc, RNA polymerase III–positive patients.

Pulmonary involvement in pediatric SSc ranges from 30% to 70% in the literature, and includes ILD, PAH (either primary, which results from vasculopathy, or secondary from ILD), and abnormal pulmonary function tests (PFTs). PFT abnormalities of special of concern are decreased forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO). ILD typically begins with an inflammatory phase, alveolitis, characterized by a mixed cellular infiltrate in the lung interstitium that spills over into the alveolar spaces. Bronchoalveolar lavage (BAL) demonstrates increased neutrophils and/or eosinophils in addition to alveolar macrophages. The presence of alveolitis is also suggested by ground-glass opacities on high-resolution computed tomography (HRCT) scans of the lungs. As ILD progresses, inflammation subsides, as there is a transition toward fibrosis with the thickening of alveolar walls and remodeling of the lung. Progressive pulmonary fibrosis may result in moderate to severe restrictive lung disease with significant decrease in FVC and DLCO. Clinically, ILD typically presents as slowly progressive dyspnea with exertion over years. In comparison, PAH presents with rapid progression of dyspnea on exertion over months. In the setting of PAH, PFTs demonstrate a decreased DLCO and abnormal echocardiogram findings with estimated pulmonary artery (PA) or right ventricular (RV) systolic pressure of greater than 40 mm Hg, verified by right-heart catheterization with mean PA pressure greater than 25 mm Hg. For most children with SSc or suspected SSc, initial assessment includes chest radiograph, PFTs, including DLCO, and an echocardiogram. Additional cardiopulmonary testing is pursued if abnormalities are detected or the patient is too young to appropriately complete testing (ie, PFTs). Abnormal PFTs prompt evaluation with HRCT of chest, and possibly BAL, if further evidence of inflammation (alveolitis) is required or evaluation of infection is needed before starting therapy. Evidence of PAH on echocardiogram is more formally assessed by right-heart catheterization.

Compared with adult-onset SSc, musculoskeletal involvement is more common in pediatric SSc. Approximately 30% to 40% of those with pediatric SSc experience inflammatory arthritis (joint effusions) in addition to the typical dry synovitis of scleroderma, reflected by the fibrosis of tendons transversing the joints, which limits their range of motion. 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. When the patient has myopathy, typically there is a symmetric proximal weakness, especially of the shoulder girdle and humeral muscles, sometimes with pronounced atrophy. Myositis is also reflected by elevated muscle enzymes and changes on magnetic resonance imaging (MRI) of muscle groups similar to those of juvenile dermatomyositis (JDM). 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.

Cardiac involvement, although infrequent, is the major cause of scleroderma-related mortality in children with SSc, and is evidenced by 10 of 15 deaths in Martini and colleagues’ cohort and 5 of 32 deaths in Scalapino and colleagues’ cohort. Cardiac manifestations result from the combination of myocardial fibrosis, vascular insufficiency, and inflammation, and include heart block, arrhythmia, congestive heart failure, cardiomyopathy, and pericarditis. In contrast to pediatric SSc, scleroderma-related mortality in adults is primarily caused by pulmonary involvement, both ILD and PAH.

Mild renal dysfunction is not uncommon in SSc and is secondary to vasculopathy instead of glomerulonephritis, which is observed in SLE. This consideration is supported by pathologic findings of intimal proliferation of the interlobular arteries of the kidney and lack of active urinary sediment (ie, red blood cell casts). By contrast, a more severe and morbid form of renal disease, scleroderma renal crisis (SRC), occurs only in approximately 15% of adult patients with SSc and is even less common in children. SRC is characterized by accelerated arterial hypertension, renal insufficiency, microangiopathic hemolytic anemia, and thrombocytopenia. In adult SSc, SRC previously had a 20% survival rate at 1 year, but now has an 80% survival rate owing to the advent of angiotensin-converting enzyme inhibitors. SRC is most frequently seen early in the disease course of dcSSc RNA-polymerase III–positive patients and is thought to be augmented by higher doses of corticosteroids. Renal crisis is rare in children with SSc, with fewer than 5% affected and only 5 cases reported (2 of whom died of renal disease) among the 3 large published cohorts.

Outcome

Despite the potential organ involvement in pediatric SSc, it has a far more favorable prognosis at 5, 10, and 15 years compared with adult SSc, with a lower frequency of severe organ involvement. Foeldvari and colleagues recently reported Kaplan-Meier survival rates at 10 years for children to be 98% versus 75% in adults. Treatment of SSc is dependent on organ involvement, but general measures such as antacid medication for GI protection, prokinetic agents for dysmotility, rotating antibiotics for malabsorption, as well as vasodilators for RP (may also help with PAH), and nonsteroidal anti-inflammatory drugs and physical therapy for arthritis or tendonitis are generally recommended. Corticosteroids for myositis, arthritis, and other inflammatory clinical features must be used with caution, as they can prompt SRC. More specific treatment recommendations for different organ manifestations have been agreed on by a consensus conference of international scleroderma experts, and were published in 2009. It is notable that in the treatment of both pediatric and adult SSc early diffuse skin disease, there has been a shift from the use of d -penicillamine to mycophenolate mofetil (MMF) likely because of its potential antiproliferative effects, although it is not included in the treatment recommendations previously discussed.