Version May 2024
INTRODUCTION — Scleroderma is a group of diseases that vary in severity and that can occur at any stage of life, although the clinical patterns of scleroderma in children differ from those in adulthood [1]. The predominant form of scleroderma in childhood is localized scleroderma. The juvenile systemic sclerosis (JSSc) form of scleroderma is uncommon but generally has more serious, potentially life-threatening morbidity than other sclerotic disorders.
Treatment is based upon disease severity, activity, and progression. However, laboratory assessment of these is difficult. Thus, regular follow-up and clinical review are the cornerstones of monitoring.
This topic reviews monitoring and management of JSSc. The classification, clinical presentation, and diagnosis JSSc are discussed in detail separately. Localized scleroderma in children and the pathogenesis of SSc are also discussed in detail elsewhere. (See "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis" and "Juvenile localized scleroderma" and "Pathogenesis of systemic sclerosis (scleroderma)".)
SSc in adults is also discussed in detail separately. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults" and "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults".)
ORGAN SYSTEM MONITORING — Many serologic markers of activity, such as intercellular adhesion molecule 1 (ICAM-1), collagen propeptides, products of type I collagen breakdown, immunologic markers (soluble interleukin 2 [sIL-2] receptor, neopterin), and vascular activation markers (E-selectin, thrombomodulin, von Willebrand factor), have been proposed throughout the years, but none have shown significant correlation with the clinical status of the patient. Thus, patients are monitored clinically rather than through laboratory markers of disease activity.
Organ systems are monitored for involvement, usually every three to four months as follows:
●Cardiovascular – Although uncommon, cardiac involvement is the leading cause of death in JSSc. Cardiac monitoring includes a standard electrocardiogram (ECG), echocardiogram, and 24-hour cardiac monitoring for arrhythmias.
ECG abnormalities include first-degree heart block, right and left bundle branch block, premature atrial and ventricular contractions, and nonspecific T-wave changes. The most frequent cardiac arrhythmias in children with JSSc are supraventricular, whereas ventricular arrhythmias are uncommon [2].
Echocardiographic abnormalities include pericardial effusions, thickening of the left ventricular wall, and decreased left ventricular compliance. The two-dimensional echocardiogram is important in confirming early pulmonary hypertension by documentation of a dilated right ventricle with thickening of the ventricular wall and straightening of the septum.
Right heart catheterization provides definitive confirmation but is indicated only in selected cases; for example, when echocardiographic data suggest a pulmonary artery hypertension.
Additional noninvasive and sensitive assessment tools for the early detection of cardiac involvement include cardiac magnetic resonance imaging (MRI) and speckle tracking strain rate (S-SR) echocardiography (STE) [3]. STE, if available, is indicated at every follow-up visit, especially in patients with a severe course of disease. Cardiac MRI is indicated when standard echocardiography or STE suggest myocardial abnormalities. As an example, myocardial fibrosis was detected using late-enhancement images (LGEs) on MRI in 15 to 66 percent of asymptomatic adult patients [4-6].
●Respiratory – Pulmonary function testing (PFT) is routinely used to detect early signs of respiratory involvement. Characteristic findings of the respiratory tract involvement include a decrease in timed vital capacity (FVC), forced expiratory flow (FEV), and diffusing capacity of the lungs for carbon monoxide (DLCO) consistent with a restrictive pattern [7]. FVC is less sensitive but more specific than DLCO in detecting potential abnormalities on high-resolution computed tomography (HRCT). Therefore, PFTs should be used in tandem with HRCT for the screening of interstitial lung disease (ILD) in JSSc [8]. The most frequent findings on HRCT are ground-glass opacification, subpleural micronodules, linear opacities, and, later in the disease process, honeycombing [9,10]. A six-minute walk test is another potential tool for monitoring pulmonary function [11].
●Gastrointestinal – Vasculopathy and inflammation leading to fibrosis can manifest in the entire gastrointestinal tract, from mouth to anus. Gastrointestinal involvement is often asymptomatic initially. Thus, imaging is necessary for diagnosis. The most common gastrointestinal problem encountered in JSSc is esophageal dysmotility, which causes poor weight gain and very low body mass index (BMI), gastroesophageal reflux disease (GERD) with acid sequela, and silent aspiration of gastrointestinal contents. Esophageal scintigraphy or cine-esophagram (barium swallow) can document decreased peristalsis in the lower part of the esophagus with distal dilation, strictures, and shortening. Esophageal manometry and 24-hour pH probe monitoring represent more sensitive indicators of diminished lower sphincter tone and presence of reflux, respectively [12]. These two studies are both performed if scintigraphy or esophagram is abnormal and the patient is able to tolerate and cooperate with the procedures.
●Skin – Skin induration is measured using the Modified Rodnan Skin Score (mRSS) (figure 1 and figure 2), corrected for BMI and the Tanner stage [13]. (See "Pretreatment evaluation of adults with systemic sclerosis (scleroderma)", section on 'Skin involvement'.)
●Microvascular – Capillary abnormalities can be detected by nailfold videocapillaroscopy (NVC) and categorized into early, active, and late stages (figure 3 and picture 1). An international consensus study reported the specific patterns NVC in children and adolescents with connective tissues diseases. This represents a useful tool for the diagnosis and assessment of JSSc [14]. The early SSc pattern is characterized by a few enlarged/ectatic capillaries and hemorrhages but normal density of capillaries. In the active stage, multiple giant and enlarged/ectatic capillaries with hemorrhages and disordered capillaries due to capillary loss are seen. The late pattern is distinguished by completely disturbed architecture with loss of multiple capillaries and bushy capillaries (neovascularization), with giant capillaries and hemorrhages only occasionally visible.
In adults, the response to treatment for Raynaud phenomenon (RP) is assessed by patient/clinician RP activity assessment, RP frequency (number of attacks per week), and RP duration (mean duration of RP attacks per week) [15]. The same approach is taken in children, although it has not been validated in any studies. Digital ulcers as a complication of RP or vasculitis can be evaluated by both digital ulcer count and degree of pain by visual analog scale (VAS). An innovative technique for RP assessment is based on the use of infrared thermography after cold challenge. This gives an indirect measure of the microvascular flow (damage) and is useful in differentiating RP secondary to SSc from primary RP and acrocyanosis if the diagnosis is in question [16].
●Musculoskeletal – Osteoarticular involvement is assessed by evaluating for the presence of arthritis, limited range of motion in the joints, and tendon friction rubs. Imaging can be used to assess for tenosynovitis, arthritis, fasciitis, myositis, and bony changes associated with arthropathy. The childhood Myositis Activity Score (c-MAS) is used to assess muscle strength (table 1) [17].
●Kidney – Kidney function is monitored by standard urine analyses and creatinine clearance with calculation of the glomerular filtration rate. Patients on glucocorticoids should have their blood pressure and kidney function carefully monitored (eg, every one to two months if the patient is on >0.5 mg/kg/day of prednisone) because of a potential increased risk of scleroderma renal crisis, particularly in patients with diffuse SSc and high or rapidly progressing skin score.
SCORING TOOLS — There is significant variability in disease severity in children. Thus, a multidimensional severity score, named "J4S," an acronym that stands for Juvenile Systemic Sclerosis Severity Score, including growth parameters, skin, and internal organ involvement, was designed to follow JSSc patients over time (table 2) [18]. The J4S includes a general category and eight organ system categories: vascular, cutaneous, osteoarticular, muscular, gastrointestinal, respiratory, cardiac, and renal. Each category is scored from 0 to 4 and then weighted based upon the clinical importance of the organ system involved. The parameters that are more sensitive to change are Raynaud phenomenon (RP), number of digital scars, and number of ulcers/gangrene for vascular involvement and the body mass index (BMI) for general assessment. J4S may have several applications for the pediatric age group since it can be used to guide decision making in daily clinical practice, compare study populations, and identify potentially reversible aspects of the disease.
Two tools that measure patient function and quality of life have been validated for children with juvenile idiopathic arthritis and juvenile dermatomyositis: the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ-PF50). Although these two instruments also appear to be excellent tools to measure clinical outcomes in children with SSc, especially in clinical trials, validation of these measures is required.
MANAGEMENT OVERVIEW — A carefully designed treatment program is based upon disease severity and progression. This multi-team approach includes [19]:
●Skin care
●Vascular protection by avoidance of cold and sudden temperature changes
●Exercise program to maintain functional ability
●Psychologic and social support
●Disease-modifying and organ-targeted pharmacologic therapy including discussions with the patient and caregiver(s) of available options
●Surgical procedures, if needed
●Education of the patient and caregiver(s) to help understand the complexity of management decisions, guide decision making, and facilitate adherence with an often difficult and time-consuming treatment plan
The pharmacologic management of patients with JSSc is challenging because the etiology and pathogenesis are poorly understood and the disease is heterogenous with variable progression [20]. The treatment of JSSc focuses on controlling symptoms and minimizing progression of internal organ involvement. No drug has been shown to be of unequivocal benefit in either children or adults with SSc, and there are no randomized trials of these therapies in children with JSSc. In addition, many of these drugs have significant side effects. As a result, careful consideration should be made on which treatment is more appropriate for each specific clinical picture, always balancing the known toxicities of the medications against the unknown possible therapeutic gain.
Options for therapeutic approaches include:
●Immunomodulatory therapy, which is directed at controlling the underlying disease process
●Organ-targeted therapy, which is directed toward complications of specifically involved organs
●Experimental therapy
GENERAL MEASURES — Nonpharmacologic measures include the following [19]:
●General skin care includes avoiding irritating or drying substances and the daily application of lanolin or water-soluble cream as an emollient.
●Patients and caregivers should be told to avoid cold, trauma, heat, and sun exposure. Cold and trauma can exacerbate symptoms. Especially in cold climates, the caregiver should keep the child warm by maintaining a satisfactory household temperature and by use of appropriate clothing, including well-insulated mittens (not gloves), boots, and a hat. These children are also susceptible to hyperpigmentation from sunlight and have difficulty in dissipating heat through sclerotic skin.
●The child should be encouraged to be as physically active as possible. Physiotherapy will help maintain functional ability, muscle strength, and joint movement while preventing flexion contractures.
●The use of corrective splints may be necessary to treat or prevent contractures.
●In patients with gastrointestinal involvement, small, frequent meals; avoiding eating before bedtime; and raising the head of the bed are advised.
IMMUNOMODULATION — An activated immune system may be an important stimulus to both fibrotic and vascular lesions in SSc. The maximum damaging effect is most likely in the early stages of the disease. Initial immune activation may create autocrine loops through the production of cytokines and growth factors, for example, which require no further stimulus to perpetuate fibrotic and vascular lesions.
Many immunotherapies are used in adults with SSc with varying degrees of efficacy. These therapies are selected case by case and usually are reserved for patients with severe, refractory diffuse cutaneous SSc (dcSSc) or overlap syndromes. The following have the most reliable efficacy and may be used in children:
●Mycophenolate mofetil – Mycophenolate mofetil (MMF) inhibits fibrosis by the direct action on fibroblasts, the inhibition of their proliferation, and the reduction of tissue accumulation of activated myofibroblasts [21]. Several observational studies have reported promising results with MMF for skin and pulmonary fibrosis [22-24]. One large observational study, including 326 patients from European centers, found that MMF was well tolerated and associated with improvement in skin disease over 12 months [25]. Another study comparing oral cyclophosphamide with MMF showed benefit for lung fibrosis and skin in both treatment arms [26].
●Glucocorticoids – High-dose systemic glucocorticoids are potentially toxic and, in adults, have been implicated in precipitating renal crisis [27]. Glucocorticoids should be restricted to patients with myositis, active fibrosing alveolitis, symptomatic serositis, the early edematous phase of the skin disease, active arthritis, and/or tenosynovitis. The lowest possible effective dose should be used in these settings, preferably below 0.3 mg/kg/day of prednisone.
●Cyclophosphamide – The role of cyclophosphamide in SSc remains uncertain. Its efficacy as a single agent is variable but, in combination with glucocorticoids or plasma exchange, is possibly efficacious in patients with fibrosing alveolitis who do not yet have advanced fibrosis [28].
ORGAN-TARGETED THERAPY — The European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) Scleroderma Trials and Research (EUSTAR) group has established evidence-based recommendations for treatment of specific organ involvement in SSc [29]. These recommendations are based upon observational studies and randomized trials in adults. However, there are no validated recommendations for JSSc. As such, a European project called Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE) was carried out to optimize and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases [30]. As part of this effort, an international committee of experts in JSSc was created for the development of specific consensus-based recommendations [31].
Surgical procedures are variable and may include orthopedic procedures for tendon release, gastrointestinal surgical treatments for severe gastroesophageal reflux disease (GERD), and calcium removal in case of tumoral calcinosis.
In the following section, we present organ-targeted treatment strategies for JSSc based upon the SHARE recommendations [31], international congresses and meetings, and adult patient guidelines [29]. Pediatric-specific literature is reviewed here. A more complete discussion on organ-based treatment for SSc is found elsewhere in multiple organ-specific topics and an overview. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults".)
Vascular involvement — Vasodilator agents are often used in patients with vascular involvement, mainly manifesting as Raynaud phenomenon (RP) and digital ulcerations or lung vascular disease (pulmonary hypertension). Specific treatment of RP is used in patients who do not respond to avoidance of precipitating circumstances such as cold or emotional stress. (See "Treatment of Raynaud phenomenon: Initial management", section on 'General measures' and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis", section on 'Raynaud phenomenon'.)
The use of vasodilator agents in patients with JSSc is rather common, especially for vasospastic phenomenon of the extremities, despite the limited published evidence. The most widely used vasodilators are the calcium channel blockers (CCBs), which have been demonstrated to reduce the frequency and severity of ischemic attacks in patients with SSc [32]. Of these, nifedipine is the most commonly used, and a sustained-release formulation is typically recommended for ease of administration. Phosphodiesterase inhibitors, specifically phosphodiesterase-5 (PDE-5) inhibitors, are an alternative for moderate-to-severe RP, typically associated with digital ulcers, or in patients unable to tolerate or who are refractory to CCB treatment. A meta-analysis of randomized, controlled trials on PDE-5 inhibitors for RP including sildenafil, tadalafil, and vardenafil demonstrated significant benefit for all agents, with reduction in frequency of RP attacks [33]. Intravenous prostanoids such as the prostaglandin, iloprost, are used if other therapy fails [29]. Data from a study on a small group of pediatric patients treated with iloprost infusions for ischemic digits and digital ulcerations suggest that these agents are effective and have a good safety profile [15]. Use of these drugs for RP is off label. Treatment of RP is discussed in greater detail separately. (See "Treatment of Raynaud phenomenon: Initial management" and "Treatment of Raynaud phenomenon: Refractory or progressive ischemia".)
Digital ulcers are another severe and disabling complication of JSSc. In view of overall risk-to-benefit considerations, CCBs and PDE-5 inhibitors are typically used as first-line therapy in SSc-related digital ulcers [32]. Prostanoids are used as first-choice treatment in rapidly progressive digital ulcers or in case of CCB resistance, with the same modalities as in severe RP [15]. Endothelin 1, a potent vasoconstrictor and smooth muscle mitogen, is a possible target in patients with digital ulcers. Bosentan, a dual endothelin receptor antagonist, is recommended in the adult SSc population both for preventing digital ulcerations and for pulmonary hypertension [29]. Little evidence is available in children regarding use of bosentan for digital ulcerations [34]. However, the SHARE experts committee agree that bosentan is an option in patients with JSSc who have digital ulcerations refractory to other therapies and/or pulmonary hypertension [31]. (See "Treatment of Raynaud phenomenon: Refractory or progressive ischemia" and "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Raynaud phenomenon'.)
Interstitial lung disease — Pulmonary alveolitis is predominant early in the course of interstitial lung disease (ILD) and later progresses to fibrosis. ILD is present in approximately one-third of JSSc patients and represents the main cause of SSc-related morbidity and death both in adults and children [35,36].
Despite this high frequency, there are no published treatment studies of ILD in children with JSSc. SHARE guidelines suggest cyclophosphamide for patients with SSc-related ILD [31] based upon two randomized trials in adults [26,37]. Despite its known toxicity, cyclophosphamide (at a dose of 500 to 750 mg/m2 once a month, maximum 1 g, intravenous pulse) is used in European pediatric scleroderma centers for JSSc pulmonary and cardiac involvement. However, most clinicians tend to use mycophenolate mofetil (MMF; 500 to 750 mg/m2/day) rather than cyclophosphamide (dosing of 1500 mg twice a day) as first-line treatment based upon comparable efficacy and better adverse effect profile (less cytopenias and infections) [37,38].
In an adult study, the use of both regimens resulted in significant improvements in prespecified measures of lung function, dyspnea, lung imaging, and skin disease [26]. As expected, MMF was better tolerated and associated with less toxicity than cyclophosphamide. The recommended length of MMF treatment is still empiric, and most experts treat at least three to four years after stabilization of lung function. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)" and "Overview of pulmonary complications of systemic sclerosis (scleroderma)" and "Approach to the infant and child with diffuse lung disease (interstitial lung disease)" and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis", section on 'Organ involvement'.)
Cardiac complications — Cardiac complications of JSSc are either primary (myocardial damage, fibrosis of the conduction system, and pericardial effusion) or secondary to pulmonary arterial hypertension [39]. Although rare, cardiac involvement is a significant cause of morbidity among children with JSSc, and cardiorespiratory complications, together with ILD, are the leading cause of death. Thus, the treatment of the cardiac complications is the same as for ILD. (See 'Interstitial lung disease' above and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis", section on 'Organ involvement'.)
Skin involvement — Despite the lack of published trials in children, the SHARE guidelines recommend the use of low-dose systemic glucocorticoids (eg, prednisone 0.3 to 0.5 mg/kg/day for two to three months) in the active inflammatory phase of the disease, usually in combination with methotrexate (at a dose of 15 mg/m2 as a single oral or subcutaneous dose per week) or an alternative disease-modifying antirheumatic drug (DMARD) [31]. The combination of systemic glucocorticoids and methotrexate is widely used in JSSc and appears to have a good safety profile. After the first three months of treatment, prednisone can be tapered down until stopping while methotrexate or the alternative DMARD is continued. In adults with SSc, results in randomized trials were inconclusive for methotrexate [40,41]. Nevertheless, the EULAR recommendations for treatment of SSc still support the use of methotrexate for skin disease [29]. (See "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis", section on 'Skin changes' and "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Skin involvement'.)
The addition of mycophenolate mofetil (MMF) is an option in patients who do not tolerate the prednisone taper and are not controlled on methotrexate alone (methotrexate-refractory disease). Studies in adults have reported positive effects, mainly on cutaneous and pulmonary involvement, with good drug tolerance [22,37,42]. MMF has proven histologic and transcription efficacy, with significant decreases in inflammatory infiltrate and microarray inflammatory gene expression profiles when comparing pre- with post-treatment skin biopsy specimens [43]. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Skin involvement' and "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)".)
Kidney disease — The prognosis for renal crisis was uniformly dismal until the introduction of angiotensin-converting enzyme (ACE) inhibitors (eg, captopril or enalapril) brought about a remarkable improvement in the outlook for prevention of vascular damage, effective long-term control of blood pressure, and stabilization of kidney function. Conversely, published evidence does not support the preventive use of ACE inhibitors to decrease the risk of development of renal crisis [29]. Management of kidney disease in SSc, including renal crisis, is discussed in detail separately. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Kidney involvement' and "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis" and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis", section on 'Organ involvement'.)
Musculoskeletal involvement — The treatment of musculoskeletal involvement (myositis, arthritis, and tenosynovitis) includes the use systemic glucocorticoids (eg, prednisone or prednisolone 0.3 to 0.5 mg/kg/day for two to three months followed by tapering down until stopping or to the minimal dose that is able to control inflammation) in combination with methotrexate. The use of potential nephrotoxins such as nonsteroidal antiinflammatory drugs (NSAIDs) should be avoided. Management of neuromuscular complications of SSc is discussed in detail separately. (See "Neuromuscular manifestations of systemic sclerosis (scleroderma)" and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis", section on 'Musculoskeletal features' and "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders" and "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Musculoskeletal involvement'.)
Gastrointestinal disease — Few studies in children with JSSc address the most effective management for gastrointestinal disease, which includes GERD, erosive esophagitis, esophageal dysmotility, diarrhea, constipation, and malabsorption due to small intestine bacterial overgrowth. GERD should be treated even in asymptomatic patients. GERD is managed in part by lifestyle and dietary changes, including nighttime routine to avoid chronic microaspiration while sleeping, which is associated with ILD in adults and children [44]. Lifestyle changes include elevating the head of the bed, avoiding meals less than three hours before bed, and eating small, frequent meals low in fat and residue with plenty of water to facilitate passage of food. Proton pump inhibitors (PPIs) are still the drugs of choice, even in the early phase of disease, for prevention of SSc-related GERD and esophageal ulcers. JSSc patients on PPIs are at increased risk of hypochlorhydria, gastric bacterial colonization, and enteric infection, in particular, Clostridium difficile, as well as hypomagnesemia and vitamin B12 malabsorption and acute interstitial nephritis; therefore, their use should be closely monitored [45,46]. The management of GERD in children is reviewed in greater detail separately. (See "Management of gastroesophageal reflux disease in children and adolescents" and "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis", section on 'Organ involvement'.)
Esophageal dysmotility is common and typically presents as dysphagia or a feeling of food getting stuck in the throat or chest area. Several studies in adults suggest that prokinetic drugs such as domperidone, erythromycin, or cyproheptadine are the preferred agents for initial therapy [47]. Low-dose erythromycin or azithromycin two to three times a day lowers esophageal pressure and increases gastric contractions to move food through the esophagus, whereas cyproheptadine assists in gut motility, gastric accommodation, and appetite stimulation [44].
Malabsorption is difficult to manage. Diarrhea and bloating are most often caused by bacterial overgrowth and are treated by rotating antibiotics because continuous therapy with one agent may result in the emergence of resistant organisms. Treatment is based upon adult SSc data. The choice of antibiotic is usually empirical and includes amoxicillin-clavulanate or oral cephalosporins. In refractory cases, metronidazole can be added for five to seven days to treat anaerobic flora [48]. (See "Treatment of gastrointestinal disease in systemic sclerosis (scleroderma)".)
Vitamins B12, vitamin D3, and iron for malabsorption and probiotics to improve bloating may be also indicated [49]. Acute intestinal pseudoobstruction can be treated with bowel rest and hydration. Constipation due to colonic sclerosis can be managed by hydration and dietary fiber.
A growing child or adolescent with SSc is vulnerable to malnutrition and growth delay. The causes can be multiple, from malabsorption or poor oral intake secondary to functional or psychological reasons. In a patient with decreasing or low body mass index (BMI) Z-score, referral to a multidisciplinary team (gastroenterologist, nutritionist, dentist, and/or mental health provider) is indicated [50].
EXPERIMENTAL THERAPY — Several drugs are under evaluation to treat different aspects of SSc in adults, including tocilizumab, rituximab, and abatacept [51,52]. Investigational agents for SSc are discussed in greater detail separately. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)", section on 'Investigational approaches'.)
A few studies in adults suggest that rituximab alone or in addition to mycophenolate mofetil (MMF) is beneficial for lung and cardiac involvement [53,54].
Only one pediatric case series of four patients treated with rituximab in addition to MMF for one year has been reported [55]. In this series, all patients showed a significant decrease in the number and duration of Raynaud phenomenon (RP) attacks and degree of cutaneous involvement. Two patients showed a global cardiac improvement and decreased severity score (J4S). The other two patients had improved respiratory function and one also resolution of arrhythmia and myositis.
Nintedanib, a tyrosine kinase inhibitor that halts fibroblast and myofibroblast proliferation and thus limits extracellular matrix accumulation, is a potential option for patients who have evidence of fibrotic lung disease on high-resolution computed tomography (HRCT). Nintedanib has been shown to slow the respiratory disease progression in adult SSc–associated interstitial lung disease (ILD) [56]. Unfortunately, nausea, diarrhea, and weight loss are common and limit its use.
One of the most aggressive approaches to therapy is immunoablation followed by reconstitution with autologous hemopoietic cell transplantation (HCT). The rationale for this therapy is the ablation of self-reactive lymphocytic clones that are potentially responsible for the disease process. Autologous HCT has shown respiratory benefit in patients with severe diffuse cutaneous SSc. The beneficial effect of HCT was demonstrated with decreased pulmonary, kidney, and cardiac morbidity in two trials, one in Europe and one in North America [57,58]. Although the mortality rate in SSc-ILD seems to improve following HCT, there remains significant initial transplant-related mortality (6 percent). This, and the high incidence of other treatment-related adverse effects, has limited its use in pediatric patients.
Based upon emerging trial data, autologous HCT may be most beneficial in selected patients with early, severe diffuse SSc. These patients may have moderate internal organ involvement and progressive disease despite an initial trial of immunosuppression. The lack of comorbidities, the more defined screening guidelines for JSSc patient selection, and the earlier referral of patients to specialized pediatric centers with expertise in both JSSc and transplantation are reasons for reconsidering HCT as a potential therapeutic strategy for children, particularly those who are early in the disease course (three years or less from the first non-Raynaud sign or symptom) before irreversible damage has occurred [59]. HCT for SSc is discussed in detail separately. (See "Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)", section on 'Autologous stem cell transplantation'.)
PROGNOSIS — In general, the prognosis of SSc in children appears better than in adults. Survival rates for childhood-onset SSc at 5, 10, 15, and 20 years after diagnosis are 89, 80 to 87, 74 to 87, and 69 to 82 percent, respectively [35,60,61]. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults", section on 'Mortality'.)
Children with SSc have two possible courses. The vast majority manifest a slow disease course with lower mortality. In these patients, JSSc is usually most active during the first three to five years following onset of disease. Typical findings include fatigue, weight loss, rapidly advancing skin induration, arthritis, myositis, and tendonitis. Visceral involvement also commonly occurs during this period. After the first five years of disease, constitutional symptoms often abate, skin abnormalities may stabilize or occasionally improve, but visceral involvement may progress.
However, approximately 10 percent of patients with JSSc have rapid development of internal organ involvement leading to severe disability and eventually to death [35,62,63]. This category includes also the sine scleroderma subtype [64].
The most common causes of death in children are related to the involvement of the cardiac, kidney, and pulmonary systems. Cardiomyopathy is a leading cause of early death, especially in children [35,63]. This complication is rare and usually associated with diffuse cutaneous disease and features of polymyositis. Aggressive immunosuppressive treatment is effective on muscle, skin, and lung involvement but may not prevent progression of myocardial dysfunction [63].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mixed connective tissue disease" and "Society guideline links: Systemic sclerosis (scleroderma)".)
SUMMARY AND RECOMMENDATIONS
●Organ system monitoring and scoring tools – Treatment is based upon disease severity, activity, and progression. However, laboratory assessment of these is difficult. Thus, regular follow-up and clinical review are used. Sequential skin scores should be recorded, and objective assessment is necessary for organ-based complications, such as pulmonary fibrosis, pulmonary hypertension, or kidney involvement. A multidimensional severity score, the Juvenile Systemic Sclerosis Severity Score (J4S), provides a more global index of severity (table 2). (See 'Organ system monitoring' above and 'Scoring tools' above.)
The modified Rodnan skin score (mRSS) is a widely accepted tool for evaluating the extent of skin fibrosis (figure 1 and figure 2). Capillary abnormalities can be detected by nailfold capillaroscopy. Gastrointestinal involvement is often asymptomatic. Thus, imaging such as esophageal technetium scintigraphy is necessary for diagnosis. The assessment of cardiac involvement is traditionally based on periodic monitoring with electrocardiography (ECG) and conventional echocardiography. The diagnosis of interstitial lung disease (ILD) in juvenile systemic sclerosis (JSSc) is based on pulmonary function tests (PFTs) and imaging.
●Management – Treatment is divided into nonpharmacologic measures and pharmacologic therapy, which includes general immunomodulation and organ-targeted therapy. (See 'Management overview' above.)
•General measures – Nonpharmacologic measures include skin care, an exercise program, and the use of corrective splints. (See 'General measures' above.)
•Immunomodulation and organ-targeted therapy – The pharmacologic management of patients with JSSc is challenging because the etiology and pathogenesis are poorly understood and the disease is heterogenous with variable progression. The treatment of JSSc is mainly symptomatic and is tailored to the individual needs of the patient based upon their specific clinical manifestations of the disease and organ involvement. No drug has been shown to be of unequivocal benefit in either children or adults with SSc, and there are no randomized trials of these therapies in children with JSSc. (See 'Immunomodulation' above and 'Organ-targeted therapy' above and 'Experimental therapy' above.)
●Prognosis – Patients with JSSc have a significant risk of severe morbidity and can have a poor prognosis. JSSc is usually most active during the first three to five years following onset of disease. After the first five years of disease, constitutional symptoms often abate and skin abnormalities stabilize or occasionally improve, but visceral involvement may progress. The overall outcome in JSSc is better than in those with adult-onset SSc, with higher survival rates seen in children. The most common causes of death in children are related to the involvement of cardiac, kidney, and pulmonary systems. (See 'Prognosis' above.)
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