Pediatric Scleroderma

Limited cutaneous systemic sclerosis (lcSSc) – The lcSSc subset presents as skin induration classically involving the fingers, sometimes extending to the hand and lower part of the arm. It also may involve the perioral area of the face and less often the feet. Involvement of the hands can be disabling, and it is exacerbated by vascular insufficiency, digital pitting scars ( picture 1), terminal bone tuft resorption ( picture 2), and digital ulcers.

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RP may be complicated with digital ulceration and, rarely, with critical ischemia leading to gangrene. Calcinosis ( picture 3) is often more severe in lcSSc than in dcSSc, and telangiectasia ( picture 4) is more widespread. Gastrointestinal involvement with esophageal dysfunction is seen at presentation. The small and large intestine may become involved later. Progressive pulmonary hypertension occurs infrequently in children but is the most common cause of death for those with lcSSc.

Systemic sclerosis-sine scleroderma – In this subset, patients have only internal organ involvement and no skin involvement. Sclerosis-sine scleroderma is rare in childhood, with only a few cases reported [5-8]. One published case described a six-year-old child who presented with nocturnal seizures, RP, and cardiopulmonary scleroderma [5]. The only cutaneous evidence of scleroderma was a slight thickening of the skin above the ankle.

The onset of JSSc is usually insidious, and the interval between onset and diagnosis in childhood is often prolonged. The majority of children with JSSc present with skin changes (tightening, thinning, and atrophy) of the hands and face and/or Raynaud phenomenon (RP) ( table 3). Other presenting complaints include arthritis, arthralgia, muscle weakness and pain, subcutaneous calcification (calcinosis), dysphagia, and dyspnea [6,13,22,23].

This was illustrated in a multicenter, retrospective study of 153 children with JSSc [13]. The median age of onset was 8.1 years, and the mean duration of symptoms prior to diagnosis was 1.9 years. Almost 80 percent of the patients were girls. Eleven percent had a family history of autoimmune disease. Symptoms or findings at diagnosis were as follows:

● RP – 70 percent

● Proximal skin induration – 63 percent

● Musculoskeletal symptoms (eg, arthralgia, muscle weakness, and arthritis) – 33 percent

● Weight loss – 18 percent

● Dyspnea – 10 percent

● Dysphagia – 10 percent

Early signs of scleroderma in children are RP, abnormal nailfold capillaroscopic findings (particularly those with "scleroderma pattern"), and positive antinuclear antibodies (ANA) with specific autoantibodies (eg, antitopoisomerase [Scl-70] or anticentromere) ( table 2 and figure 1). These manifestations may precede by years the full spectrum of JSSc manifestations [24,25]. Children with these findings should be followed up more closely since they are at increased risk of developing JSSc, although the majority do not.

Raynaud phenomenon — The primary vascular complication of SSc is RP. The classical Raynaud attack consists of three phases. The first represents vasoconstriction, where the fingers turn white. This is followed by a bluish discoloration. Then, with reperfusion, a reddish discoloration occurs. These findings primarily occur distal to the proximal interphalangeal joint on the fingers, and the thumbs are usually spared. RP is more common in the fingers but can be observed in the toes, ears, lips, tongue, and the tip of the nose. RP can result in digital ulceration and critical ischemia leading to gangrene.

Capillary abnormalities — The periungual nailfold is the most accessible site for detection of nailfold capillary abnormalities. Examination with an ophthalmoscope may demonstrate capillary dropout, tortuous dilated loops, and occasionally distorted capillary architecture ( figure 1 and picture 5) [26,27]. Telangiectasia is less commonly present in children than adults with JSSc ( picture 4).

Skin changes — Skin changes characteristically evolve in the following sequence:

• Edema
• Induration and edema, resulting in skin tightening and contractures
• Atrophy

Patients with JSSc often present with swollen hands or feet ( picture 6), which can mimic polyarticular juvenile idiopathic arthritis. The edema may persist for weeks to months before skin changes as a result of sclerosis and/or RP emerge. The induration usually progresses bilaterally with variable speed and without clear demarcation and may last from three to five years. The residual atrophic phase persists as an integral part of the disease process.

During the atrophic phase, the skin becomes sclerotic (waxy in texture, tight, and hard) and bonds to subcutaneous structures. This is particularly noticeable over the distal digits and face.

The loss of adnexal structures leads to a shinier, smoother appearance, with the face often developing an unwrinkled, immobile, and expressionless appearance with limited oral aperture. The characteristic facial appearance may be the first clue to the diagnosis.

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Musculoskeletal features — Musculoskeletal involvement is common and characteristically occurs at or shortly after disease onset [12,27].

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Arthralgia is usually mild and transient. It is the presenting symptom in approximately 15 percent of children [13].

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Joint contractures are most common at the proximal interphalangeal joints and elbows.

Arthritis and myositis may occur in up to 30 percent of children and are characteristic of the overlap subset of SSc rather than representing a general precursor to JSSc. Myositis leads to muscle weakness and myalgia and is associated with elevated levels of creatine kinase (CK). Since myocarditis may also occur, children with significantly elevated CK should be appropriately evaluated.

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Periarticular and subcutaneous calcinosis may occur in one-fifth of patients [13], whereas bone resorption is uncommon in children and adolescents [28].

Gastrointestinal disease – During the disease course, gastrointestinal involvement is reported to occur in 30 to 74 percent of children with JSSc [6,13,29]. Most affected patients have esophageal dysfunction, resulting in gastroesophageal reflux and dysphagia. Large bowel involvement may present as alternating complaints of constipation and diarrhea, bloating, abdominal discomfort, or malabsorptive stools. (See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)".)

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Growth represents a major concern as poor weight gain or weight loss are reported in 14

to 18 percent of patients [13,29].

Radiologic and functional studies of the gastrointestinal tract often demonstrate abnormalities even in the absence of symptoms. Manometry and intraesophageal 24-hour pH monitoring are sensitive indicators of diminished lower esophageal sphincter tone and gastroesophageal reflux disease (GERD) [30]. However, esophageal scintigraphy scan is the preferred tool to evaluate and monitor GERD and esophageal dysmotility because it is faster and less invasive

Pulmonary disease – Patients with pulmonary involvement are frequently asymptomatic initially but eventually present with dyspnea, although some may present with a dry, hacking cough [31]. Interstitial lung disease (ILD) has been reported in 30 to 50 percent of children with JSSc, whereas pulmonary fibrosis, which represents the final irreversible stage of ILD, is common in adults with SSc but rarely reported in children [6,13,29].

Pulmonary vascular disease occurs either independently or as a result of pulmonary fibrosis in less than 4 percent of patients [6]. Although rare, early diagnosis and therapy are important as severe lung disease is one of the major causes of death in children with JSSc.

Screening tests for pulmonary disease in children with JSSc include, in order, pulmonary function studies, chest radiograph, high-resolution computed tomography (HRCT), and echocardiography. Some also use a six-minute walk test to assess pulmonary function.

High-resolution computed tomography – HRCT may reveal pulmonary disease even in the presence of a normal chest radiograph. In children with JSSc, HRCT findings may include ground glass opacification, subpleural micronodules, and linear opacities consistent with ILD and honeycombing appearance consistent with pulmonary fibrosis [36-38]. An HRCT of the chest is usually obtained at disease onset and repeated if pulmonary function testing becomes abnormal.

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Echocardiography – Echocardiography is important for detecting pulmonary arterial hypertension (PAH), which is defined as a mean pulmonary artery pressure greater than 25 mmHg at rest or greater than 30 mmHg during exercise [39].

Echocardiography is typically performed at disease onset and then repeated if the patient develops sign/symptoms of cardiac dysfunction, arrhythmia, or abnormal pulmonary function testing.

Pulmonary function studies – Pulmonary diffusion (diffusion capacity of the lungs for carbon monoxide [DLCO]) and spirometry are sensitive measures of involvement of the respiratory tract and are used as a screening test for pulmonary disease in children with JSSc. These studies may be abnormal despite normal chest radiographs. (See "Overview of pulmonary function testing in children".)

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Chest radiograph – The chest radiograph should not be used as a screening test for intrinsic pulmonary disease in children with JSSc, due to its low sensitivity in revealing early signs of lung involvement. The classic radiographic feature only appears when an advanced degree of ILD is present and consists of symmetric, reticulonodular shadowing, most pronounced at the lung bases. However, a chest radiograph is a useful tool to assess for comorbidities such as infection and pleural effusion.

Cardiac involvement – Clinically evident cardiac involvement in JSSc is rarely reported, with a frequency ranging between 5 and 24 percent [40]. Although uncommon, cardiac involvement is a significant cause of morbidity among children with JSSc, and cardiorespiratory complications are the leading cause of death [6,13,32-34]. Cardiac complications of JSSc are either primary (myocardial damage, fibrosis of the conduction system, and pericardial effusion) or secondary to PAH [41]. Cardiac fibrosis may lead to conduction defects, arrhythmias, cardiomyopathy, and impaired ventricular function. Pericardial effusions are common but are not usually of hemodynamic significance. Isolated cardiac disease is rare. More frequently, cardiac and pulmonary involvement appear as one complex of organ involvement where changes in one cause changes in the other. As an example, PAH caused by pulmonary vascular disease or fibrosis can lead to myocardial damage and right heart failure. (See "Cardiac manifestations of systemic sclerosis (scleroderma)".)

Renal involvement – The reported prevalence of renal crisis in children with JSSc ranges from 0.7 to 4 percent [6,13,29]. In a case series of 153 children with JSSc, approximately 10 percent had renal involvement (such as proteinuria, hematuria, or progressive renal failure), but there was only one child with acute renal crisis, accelerated hypertension, and renal failure [13]. Although renal involvement in children is generally not as severe as what is seen in adult patients, the abrupt onset of accelerated hypertension with acute kidney injury (scleroderma renal crisis) is a severe and life-threatening complication.

DIAGNOSIS

The diagnosis of JSSc in childhood is often delayed because of its rarity and the subtle initial manifestations. The diagnosis is established clinically by the presence of typical skin thickening and hardening (sclerosis) that is not confined to one area (ie, not localized scleroderma) and visceral involvement. The diagnosis is further supported by the presence of associated autoantibodies.

In 2007, a multicenter, multinational group representing the Paediatric Rheumatology European Society (PRES), the American College of Rheumatology (ACR), and the European Alliance of Associations for Rheumatology (EULAR; formerly known as the European League Against Rheumatism) defined nomenclature and criteria to diagnosis and classify JSSc based upon clinical features and laboratory parameters [2]. In a patient less than 16 years of age, JSSc is diagnosed if the major criterion and at least 2 of 20 minor criteria listed in the table

( table 1) are present [2]. The classification criteria for SSc in adults were revised in 2013 in order to identify patients at an earlier stage of the disease, thereby enabling earlier treatment [43]. According to these new criteria ( table 4), the presence of skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient to classify the patient as having SSc. However, in the absence of this sign, patients are evaluated for seven alternative weighted criteria (each ranging from two to four points; patients with a score ≥9 are classified as SSc). The adult criteria have not been validated in children. However, these criteria may be helpful in children who do not have a clear diagnosis using the JSSc criteria. (See 'Classification' above.) An evaluation of a cohort of patients with JSSc followed at the Pediatric Rheumatology Division of the University of Padua showed that 84 percent were classified as having JSSc using the 2013 ACR/EULAR adult SSc criteria compared with 68 percent using the 2007 PRES/ACR/EULAR provisional JSSc criteria [44]. This finding suggests that the provisional pediatric criteria are too specific, at the cost of sensitivity for early disease manifestations.

MANAGEMENT OVERVIEW

A carefully designed treatment program is based upon disease severity and progression. This multi-team approach includes [17]:

• ●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 [18]. 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 or observational studies of these therapies in children with JSSc. In addition, many of these drugs have significant side effects. As a result, careful consideration must be made as to whether or not to initiate treatment, including 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 [17]:

●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 – Several observational studies have reported promising results with mycophenolate mofetil (MMF) for skin and pulmonary fibrosis [19-21]. 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 [22]. Another study comparing oral cyclophosphamide with MMF showed benefit for lung fibrosis and skin in both treatment arms [23].

●Glucocorticoids – High-dose systemic glucocorticoids are potentially toxic and have been implicated in precipitating renal crisis [24]. 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 [25].

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 [26]. 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 [27]. As part of this effort, an international committee of experts in JSSc was created for the development of specific consensus-based recommendations.

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 preliminary reports of SHARE experts in International Congresses and meetings and adult patient guidelines [26]. 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). Of these, nifedipine is the drug most commonly used. An alternative to CCBs is a phosphodiesterase type 5 inhibitor (PDE-5i) such as sildenafil. In view of costs and feasibility, CCBs or PDE-5i are used as first-line drugs when pharmacotherapy is needed in the treatment of RP in children with JSSc. Intravenous prostanoids such as the prostaglandin, iloprost, are used if other therapy fails [26]. 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 [13]. 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-5i are typically used as first-line therapy in SSc-related digital ulcers [28]. 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. 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 [26]. Little evidence is available in children regarding use of bosentan for digital ulcerations [29]. 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. (See "Treatment of Raynaud phenomenon: Refractory or progressive ischemia" and "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults".)

Interstitial lung disease — Pulmonary alveolitis is predominant early in the course of interstitial lung disease (ILD) and later progresses to fibrosis. EULAR guidelines suggest cyclophosphamide for adult patients w

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 [31]. Although rare, cardiac involvement is a significant cause of morbidity among children with JSSc, and cardiorespiratory complications are the leading cause of death. Thus, cardiac involvement requires prompt and aggressive immunosuppressive therapy. Some patients may also need a pacemaker for arrhythmia. 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 data in children, there is a general consensus on 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 (15 mg/m2 as a single oral or subcutaneous dose per week) or an alternative disease-modifying antirheumatic drug (DMARD). The combination of systemic glucocorticoids and methotrexate is widely used in JSSc, especially in skin, subcutaneous, and articular involvement, and appears to have a good safety profile. After the first three months of treatment, prednisone is tapered down until stopping while methotrexate or the alternative DMARD is continued. In adults with SSc, results in randomized trials were inconclusive for methotrexate [32,33]. Nevertheless, the EULAR recommendations for treatment of SSc still support the use of methotrexate for skin disease [26]. (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 [19,30,34]. Cyclophosphamide is not indicated for isolated skin involvement. (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)".)

Renal 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 renal function. Conversely, published evidence does not support the preventive use of ACE inhibitors to decrease the risk of development of renal crisis [26]. Management of renal 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'.)

Hemodialysis with or without bilateral nephrectomy and transplantation was an option in cases of irreversible renal failure or uncontrollable hypertension. However, the advent of ACE inhibitors makes this of primarily historic interest.

Musculoskeletal involvement — The treatment of musculoskeletal involvement (myositis, arthritis, and tenosynovitis) includes the use systemic glucocorticoids (eg, prednisone/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".)

Gastrointestinal disease — Few studies in children with JSSc address the most effective management for gastrointestinal disease, which includes GERD, erosive esophagitis, and malabsorption due to bacterial overgrowth. 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 [35,36]. 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'.)

Several studies in adults suggest that prokinetic drugs such as domperidone may improve gastrointestinal signs and symptoms (dysphagia, early satiety, bloating, pseudo-obstruction) in SSc patients [37]. There are no published data on efficacy in children, but these drugs are sometimes used when other measures have failed.

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 [38]. Hyperalimentation may be necessary but is not an effective long-term choice [37]. (See "Treatment of gastrointestinal disease in systemic sclerosis (scleroderma)".)