Scleroderma in children

Best Practice & Research Clinical Rheumatology xxx (2018) 1e20

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Scleroderma in children Francesco Zulian Division of Pediatric Rheumatology, Department of Woman and Child Health, University of Padua, Padua, Italy

a b s t r a c t Keywords: Juvenile systemic sclerosis Juvenile localized scleroderma Classification Assessment Monitoring Severity score Outcome measures Treatment Outcome

Juvenile scleroderma with its two varieties, juvenile localized scleroderma and systemic sclerosis (SSc), represents the third most frequent rheumatic disease in childhood. In juvenile SSc, new developments have been recently reported in the fields of classification and monitoring. The introduction of new classification criteria for adult SSc has stimulated new ideas on how to improve the performance of the provisional 2007 PRES/ACR/EULAR pediatric criteria. The introduction of a multidimensional severity score, named “J4S,” which includes parameters on growth, skin, and internal organ involvement, has improved the approach to the patients in the daily practice to guide decision-making. In localized scleroderma, the wider application of clinical and instrumental scoring systems has greatly improved both assessment and monitoring. Finally, a multicenter consensus statement and long-term follow-up studies have confirmed the important role of methotrexate for the treatment. © 2018 Elsevier Ltd. All rights reserved.

Juvenile scleroderma represents the third most frequent rheumatic condition in childhood after juvenile idiopathic arthritis and systemic lupus erythematosus (SLE). The two main forms of the disease are juvenile localized scleroderma (JLS) and juvenile systemic sclerosis (JSSc). JSSc is a multisystem connective tissue disorder characterized by fibrotic skin changes and abnormalities of internal organs. JSSc has a variety of clinical manifestations, sometimes different from the adult form. In general, the overall outcome is better in children, although, in some cases, the disease progression is rapid and severe due to the early involvement of internal organs.

E-mail address: [email protected]. https://doi.org/10.1016/j.berh.2018.02.004 1521-6942/© 2018 Elsevier Ltd. All rights reserved.

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F. Zulian / Best Practice & Research Clinical Rheumatology xxx (2018) 1e20

JLS, otherwise called as morphea by some dermatologists, represents the most frequent condition in childhood and comprises a group of distinct clinical entities that involve the skin and subcutaneous tissues. The clinical manifestations range from very small plaques of induration to large and deep skin lesions that may cause significant functional and cosmetic deformities. Juvenile systemic sclerosis JSSc is a multisystem connective tissue disease characterized by hardening skin changes and widespread abnormalities of the viscera. The PRES-ACR-EULAR 2007 classification criteria require the presence of skin sclerosis/induration proximal to metacarpalphalangeal (MCP) or metatarsalphalangeal (MTP) joint and at least two of 20 minor criteria listed in Table 1 [1]. More recently, a review of the classification criteria for systemic sclerosis in adults was made [2]. According to these new criteria, 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, seven alternative criteria (i.e., skin thickening of the fingers, fingertip lesions, telangiectasias, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon (RP), and SSc-related autoantibodies) are to be considered indicative. Each of these items has a different weight in defining SSc, and patients with a score
9 can be classified as having SSc. These criteria might also be applicable to JSSc patients, although some essential differences between the two age groups and the possible weak discrimination power with other pediatric conditions which enter in the differential diagnosis must be borne in mind. An evaluation of a cohort of patients with JSSc may serve as an example of how the existing classifications are still inadequate (personal data by the Author). Since 2011, 25 new patients with JSSc have been examined at the Pediatric Rheumatology Division of the University of Padua and 21 (84%) could be classified as having jSSc using the 2013 ACR/ EURLAR adult SSc criteria as compared to 17 (68%) using the 2007 PRES/ACR/EULAR JSSc criteria. In all cases, the failure to meet the provisional criteria was due to a failure to meet the major criterion [3]. This calls to question whether the provisional criteria are too specific, at the cost of sensitivity for early disease manifestations.

Table 1 PRES/ACR/EULAR Provisional classification Criteria for Juvenile Systemic Sclerosis. Adapted from reference no. [1]. MAJOR CRITERION MINOR CRITERIA

- Skin - Vascular

- Gastrointestinal - Renal - Cardiac - Respiratory

- Musculo skeletal

- Neurological - Serology

Sclerosis/induration of the skin proximal to MCP or MTP joints Sclerodactyly Raynaud's phenomenon Nailfold capillary abnormalities Digital tip ulcers Dysphagia Gastroesophageal reflux Renal crisis New-onset arterial hypertension Arrhythmias Heart failure Pulmonary fibrosis (HRCT/X-ray) DLCO Pulmonary hypertension Tendon friction rubs Arthritis Myositis Neuropathy Carpal tunnel syndrome Antinuclear antibodies. SSc selective autoantibodies (anticentromere, antitopoisomerase I, anti-fibrillarin, anti-PM-Scl, anti-fibrillin or anti-RNA polymerase I or III)

A patient, aged less than 16 years, shall be classified as having juvenile systemic sclerosis if the one major and at least two of the 20 minor criteria are present. This set of classification criteria has a sensitivity of 90%, a specificity of 96% and kappa statistic value of 0.86.

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Epidemiology Onset of systemic sclerosis in childhood is uncommon. A study from the United Kingdom reported an annual incidence rate of 0.27 per million children under the age of 16 years [4]. It has been estimated that approximately 3% of all patients with systemic sclerosis had onset in childhood and patients aged 10e20 years account for only 1.2e9% of all cases [5]. JSSc occurs with equal frequency in boys and girls younger than 8 years old, whereas girls outnumber boys in a proportion of 3 to 1 when disease onset occurs in children who are older than 8 years [6]. Etiology and pathogenesis The cause of SSc is unknown despite significant advances in the understanding of potential pathogenetic mechanisms. The disease can be represented as a tripartite process in which dysfunction of the immune system, endothelium, and fibroblasts gives rise to a heterogeneous phenotype that is characterized prominently by fibrosis. As for the genetic component, the familial occurrence of JSSc is very rare [7], and only one report described JSSc in monozygotic twins [8]. Microchimerism, defined as the presence within one individual of cells derived from a different individual, was postulated as a possible cause of scleroderma. Microchimerism occurs in women who had previous pregnancies, individuals who have had blood transfusions, and children with cells from the mother or from a twin. These findings may support the hypothesis that fetal anti-maternal (or anti-unrelated individual) graft-vs-host reactions might be involved in the pathogenesis of SSc [9]. This fascinating hypothesis, however, cannot explain the occurrence of scleroderma in men or in women who have never had children. A recent study investigating the expression of HLA class II alleles in patients with JSSc showed that DRB1*10 is significantly increased and confirmed the importance of the HLA class II region in this disease [10]. Clinical manifestations Early signs and symptoms: The onset of the disease is usually insidious. Isolated RP is often the presenting feature along with positive antinuclear antibodies (ANA) and nailfold capillaroscopy changes. Months or years later, tightening of the skin, especially of fingers and face, appearance of cutaneous telangiectases, and symptoms related to internal organ involvement gradually develop [6]. Because of the subtle nature of this presentation, there is often a diagnostic delay of years [11,12]. Sometimes, early JSSc may mimic juvenile polyarthritis, as patients often present with swollen hands or feet. These symptoms may persist for weeks before skin induration, and other more specific symptoms emerge. The main signs and symptoms of JSSc are summarized in Table 2. Cutaneous changes characteristically evolve in a sequence beginning with edema, followed by induration and eventually atrophy. During the sclerotic phase, the skin develops a waxy texture and becomes tight and bound to subcutaneous structures. This is particularly noticeable at the level of digits, the so-called sclerodactyly (Fig. 1), and the face. The characteristic expressionless, unwrinkled appearance of the skin may be the first clue to the diagnosis (Fig. 2). These superficial abnormalities result in a shiny appearance of the skin accompanied by areas of hypo- or hyperpigmentation. Telangiectasia is less commonly present in children than in adults. Nailfold capillary abnormalities are common, and the examination of the periungueal nailfold with an ophthalmoscope may demonstrate capillary dropout, tortuous dilated loops, and distorted capillary architecture [13,14]. Digital pitting, sometimes with ulceration and gangrene, occurs in the pulp of the fingertips as a result of a distal artery ischemic event. Subcutaneous calcification, especially over the elbows, MCP joints and knees, occur in one-fifth of the patients, sometimes with ulceration of the surrounding skin. Musculoskeletal symptoms are common and characteristically occur at or near the disease onset in one-third of children with JSSc [6]. Morning stiffness, arthralgias, and arthritis are often the initial manifestations of the disease. Arthritis and myositis may occur in up to 30% of children and are characteristic of the overlapping manifestations that may precede the diagnosis of JSSc [12]. Please cite this article in press as: Zulian F, Scleroderma in children, Best Practice & Research Clinical Rheumatology (2018), https://doi.org/10.1016/j.berh.2018.02.004

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F. Zulian / Best Practice & Research Clinical Rheumatology xxx (2018) 1e20 Table 2 Clinical features of Juvenile Systemic Sclerosis at the time of diagnosis and during the overall course of the disease. (adapted from reference no. [6]).

Skin Sclerodactyly Skin induration Calcinosis Peripheral vascular system Raynaud's phenomenon Digital infarcts Digital pitting Abnormal capillaroscopy Respiratory system Dyspnea Abnormal chest X-ray Abnormal chest HRCT Reduced DLCO Cardiac involvement Pericardial effusion Heart failure Pulmonary hypertension Musculo-skeletal system Muscle weakness Arthritis Arthralgia Tendon friction rubs Gastrointestinal system Dysphagia Gastroesophageal reflux Diarrhea Weight loss Renal system Raised creatinine/proteinuria Renal crisis Hypertension Nervous system Peripheral neuropathy Abnormal brain MRI

At diagnosis

Overall course

%

%

45.8 73.9 9.3

66.0 82.4 18.5

74.7 18.8 28.0 24.7

84.2 28.9 38.0 51.7

9.9 12.1 4.7 8.0

17.9 28.9 23.0 26.7

5.2 2.0 1.3

9.8 7.3 7.2

12.0 17.3 26.4 5.6

24.3 27.0 36.0 11.3

9.9 8.0 1.3 18.0

23.7 30.0 9.9 27.2

3.3 0.0 1.3

5.2 0.7 2.6

0.6 1.9

0.6 2.6

Gastrointestinal involvement affects one-third of the patients but is much more frequent if the diagnosis is made using a device [6,12]. Esophageal scintiscan, intraesophageal 24-hour pH monitoring, and manometry are sensitive indicators of diminished lower esophageal sphincter tone and gastresophageal reflux [15]. Although the esophagus is involved often quite early in the disease course, many patients are asymptomatic and rarely present heartburn or dysphagia. Small-bowel involvement usually develops in association with esophageal or colonic disease. Malabsorptive diarrhea and delayed colonic transit, when present, reflect long-standing disease. Cardiopulmonary involvement is the leading cause of morbidity and mortality in JSSc [16,17]. Cardiac fibrosis may lead to conduction defects, arrhythmias, and impaired ventricular function. Isolated cardiac disease is rare. More frequently, cardiac and pulmonary involvement appears as one complex organ involvement where changes in one cause changes in the other. In the largest published study on JSSc, cardiac involvement was found in 8.4% of cases at the disease onset and in 24% during the overall course [6]. Cardiac involvement is one of the major prognostic factors in JSSc as the cause of death in 50.0% of deceased patients, and pericarditis was recognized as the major predictor of mortality (odds ratio 41.3) [16]. Severe cardiomyopathy, although rare, requires prompt and aggressive immunosuppressive therapy [17]. Pulmonary involvement is initially asymptomatic but, later on, it may be revealed by dry, hacking cough or dyspnea on exertion. Pulmonary artery hypertension occurs in a minority of JSSc patients and, Please cite this article in press as: Zulian F, Scleroderma in children, Best Practice & Research Clinical Rheumatology (2018), https://doi.org/10.1016/j.berh.2018.02.004

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Fig. 1. Sclerodactyly with sparse telangiectases in a 13-year-old teenager with limited variety of systemic sclerosis.

as in adults, may be an isolated vascular complication or consequence of pulmonary fibrosis [6,12]. Unlike adults, interstitial pulmonary fibrosis is rarely reported in children with JSSc [6,12]. Screening tests for pulmonary disease include pulmonary function tests, chest radiograph, and high-resolution computed tomography (HRCT). The HRCT may be abnormal despite normal chest radiographs that become abnormal in case of initial interstitial lung disease. HRCT may reveal pulmonary disease even in the presence of a normal chest radiograph, with ground-glass opacification (Fig. 3), subpleural micronodules, linear opacities, and honeycomb appearance. Renal involvement is present in less than 5% of JSSc patients and is mainly characterized by increased urinary protein secretion, increased creatinine level and, rarely, renal crisis [6]. This is a severe and life-threatening complication that consists of abrupt onset of hypertension and acute renal failure. Because in adult patients the presence of antitopoisomerase I antibody, rapidly progressing skin involvement, and high-dose steroids are predictors of severe renal and cardiac involvement [18], a close monitoring of blood pressure and renal function in patients treated with corticosteroids is recommended. Differences from adult disease Compared to adults, at diagnosis, children show a significantly less frequent involvement of the internal organs, while the prevalence of arthritis is similar [6,12,19]. Differences from adults become less evident during the disease course with the exception of interstitial lung involvement, gastroesophageal dysmotility, and renal involvement, which are significantly much more common in adults. Arthritis and muscle inflammation are slightly more common in children as an expression of the increased prevalence of overlap syndromes [12]. Autoantibodies High-titer ANA is frequently present (81e97%) because the disease onset and the predominant patterns, on HEp-2 cell substrate, are speckled and nucleolar [6,12]. Antitopoisomerase I (anti-Scl-70) autoantibodies are present in 28e34% of patients, while the prevalence of anticentromere antibodies (ACAs) is much lower than in adult SSc (7% vs 23%) [6,19]. Anti-PM-Scl and anti-U1RNP antibodies correlate with scleroderma in overlap syndromes with musculoskeletal involvement. Anti-RNApolymerase III antibody is very unusual, in parallel with the rarity of renal involvement in JSSc [12]. The frequency of rheumatoid factor (RF) and anti-cardiolipin antibodies (aCLs) is similar to that of the adult SSc, i.e., 17% and 14.8%, respectively [6,19]. Please cite this article in press as: Zulian F, Scleroderma in children, Best Practice & Research Clinical Rheumatology (2018), https://doi.org/10.1016/j.berh.2018.02.004

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Fig. 2. Classical expressionless appearance of a 14-year-old teenager with systemic sclerosis. Note the waxy and shiny appearance of the skin.

Fig. 3. Computed tomography (CT) of the chest shows peripheral basilar subpleural ground-glass opacity, typical of nonspecific interstitial pneumonia.

Clinical assessment and monitoring The assessment of disease activity and severity in JSSc is quite important, and during the last few years, objective scoring methods have been proposed. Electrocardiographic 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 are supraventricular, whereas ventricular arrhythmias do not Please cite this article in press as: Zulian F, Scleroderma in children, Best Practice & Research Clinical Rheumatology (2018), https://doi.org/10.1016/j.berh.2018.02.004

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occur very often [20]. Echocardiographic abnormalities, in addition to pericardial effusions, include 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. Although uncommon, the cardiac involvement is the leading cause of death in JSSc, and therefore, an accurate periodical monitoring is mandatory and should include standard EKG, echocardiogram, and 24-hour cardiac monitoring for arrhythmias. More recently, following the experience in SSc patients, new assessment tools such as cardiac magnetic resonance imaging (MRI) and speckle tracking strain rate (SSR) echocardiography have been introduced. They are noninvasive and sensitive tools for the early detection of cardiac involvement. As an example, the prevalence of myocardial fibrosis in asymptomatic adult patients, detected with late enhancement images (LGE) on MRI, was found ranging between 15% and 66% [21e23]. Characteristic findings of the respiratory tract involvement include a decrease in timed forced vital capacity (FVC), forced expiratory flow (FEV), and CO diffusion (DLCO) consistent with a restrictive pattern [24]. These pulmonary function tests are routinely used as an early indication of respiratory involvement. In case of abnormality, the HRCT may confirm the presence of pulmonary disease, in which the most frequent findings are ground-glass opacification, subpleural micronodules, linear opacities, and, as late aspect, honeycombing [25]. Gastrointestinal involvement, assessed by cine-oesophagogram or more easily by scintigraphy, may 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 [15]. Skin involvement can be quantified by the modified Rodnan skin score (mRSS). Capillary abnormalities can be detected by nailfold capillaroscopy [26], while the RP can be monitored by using infrared thermography after cold challenge. This gives an indirect measure of microvascular flow and is useful in differentiating RP secondary to SSc from primary RP and acrocyanosis [27]. A multidimensional severity score, named “J4S,” an acronym which stands for Juvenile Systemic Sclerosis Severity Score, including growth parameters, skin, and internal organ involvement, has been proposed to follow JSSc patients overtime [28] (Table 3). This instrument includes nine categories, each one scored from 0 to 4, weighting various organ involvements on the basis of their clinical importance. J4S evaluates the disease severity that includes a combination of both reversible (activity) and irreversible (damage) components that are closely related to each other. J4S may have several applications for the pediatric age group because it can be used in the daily clinical practice to guide decision-making and to compare study populations. Treatment The pharmacological management of JSSc is challenging because no drug has been shown to be of unequivocal benefit in either children or adults with systemic sclerosis. Owing to paucity of evidence in children, recommendations need to be extrapolated from adult data [29,30] (Fig. 4). The cardinal point for the treatment of the vascular complications such as RP and/or digital ulcers is the use of vasodilators. As first-line therapy, calcium channel blockers such as oral nifedipine are indicated [30]. For refractory cases of severe RP with critical ischemic digits or digital ulcers, phosphodiesterase type 5 (PDE-5) inhibitors should be considered [30]. Studies demonstrated that iloprost, an analog of natural prostacyclin (PGI2), reduces the frequency and the severity of ischemic attacks and digital ulcers [31,32]. Bosentan, an endothelin receptor antagonist, is advised for the prevention of digital ulcers when calcium channel blockers or prostanoids fail or are contraindicated [30,33,34]. At the time of diagnosis of JSSc, low-dose methotrexate should be introduced, especially in case of skin, subcutaneous, and articular involvement [30]. With the same indications, mycophenolate mofetil may be a good alternative to methotrexate, especially in refractory disease or in case of methotrexate intolerance [35]. Cyclophosphamide represents the drug of choice for the treatment of interstitial lung disease, in particular for those patients with rapidly worsening course [30]. According to the experience in Please cite this article in press as: Zulian F, Scleroderma in children, Best Practice & Research Clinical Rheumatology (2018), https://doi.org/10.1016/j.berh.2018.02.004

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Generala Vascular Skin Osteo Articularb Muscleb Gastro Intestinala

Respiratorya,c

Cardiaca,c

Renald

0 Normal

1 Mild

2 Moderate

3 Severe

4 END STAGE

Maximum score

BMI
to the baseline value Hb > 11.5 g/dl no RP MRSS 0 No articular involvement

BMI <1st centile Hb 10e11.4 g/dl RP requiring vasodilators MRSS 1-14

BMI <3rd centile Hb 7e8.9 g/dl Digital tip ulcerations MRSS 30-39

4 4 2

cMAS 39-51

cMAS 13-25

BMI <4th centile Hb < 7 g/dl Digital gangrene MRSS > 40 presence of arthritis and/or tendon friction rub cMAS 0-12

4

Normal proximal muscle strength Normal prox GI tract investigations

BMI <2nd centile Hb 9e9.9 g/dl Digital tip scars MRSS 15-29 presence of limited range of motion (ROM) cMAS 38-26

2

Medium and/or high esophageal hypoperistalsis

Malabsorption syndrome

Hyper alimentation

4

DLCO > 80% FVC > 80% Normal HRCT sPAP < 30 mmHg Normal EKG

GI symptoms Distal esophageal hypoperistalsis GERD at 24-hour Ph-metry or scintiscan DLCO 70e79% FVC 70e79% Alveolitis on HRCT sPAP 31e45 mmHg EKG conduction defect

DLCO 50e69% FVC 50e69% Fibrosis on HRCT sPAP 46e75 mmHg Arrhythmia

O2 Dependence

8

CHF

8

LVEF >50% Creatinine clearance (GFR): >90 ml/min

LVEF 45e49% Creatinine clearance (GFR): 75e89 ml/min

LVEF 40e44% Creatinine clearance (GFR): 50e74 ml/min

DLCO < 50% FVC < 50% Fibrosis on X-ray sPAP > 75 mmHg Arrhythmia requiring treatment LVEF 30e40% Creatinine clearance (GFR): 10e49 ml/min

LVEF < 30% ESRF

4

BMI: body mass index; DLCO: diffusing capacity for carbon monoxide; LVEF: left ventricular ejection fraction; Hb: hemoglobin; FVC: forced vital capacity; CHF: congestive heart failure; MRSS: modified Rodnan Skin Score; cMAS: childhood muscle activity score; sPAP: estimated pulmonary artery systolic pressure by Doppler echo; GFR: glomerular filtration rate; ESRF: endstage renal failure; GERD: gastroesophageal reflux disease; EKG: electrocardiogram. a Either one of the following parameters defines the score. b Each score should be multiplied by 0.5 to obtain the final score. c Each score should be multiplied by 2 to obtain the final score. d GFR: male 0e12 y ¼ 0.55  height (cm)/creatinine (mg/dl); male 12e18 y ¼ 0.7  height (cm)/creatinine (mg/dl); female 0e18 y ¼ 0.55  height (cm)/creatinine (mg/dl); male > 18 y ¼ (weight in Kg  140) e age (years)/72  creatinine (mg/dl); female > 18 y ¼ [(weigh in Kg  140) e age (years)/72  creatinine (mg/dl)] * 0.85.

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Table 3 The juvenile systemic sclerosis severity score (J4S). (adapted from reference no. [28]).

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Fig. 4. Proposed flowchart for the management of juvenile systemic sclerosis.

juvenile SLE, it should be administered as intravenous pulse therapy at a dosage of 0.5e1 g/m2 every 4 weeks for at least 6 months [36]. Its efficacy, although moderate, was proved by several randomized controlled trials in adults [37]. However, its short-term (leukopenia and infections) and long-term (infertility, carcinogenesis, and bone marrow depression) toxicities represent limits for its wide use in the pediatric population and thus should be closely monitored. The safety profile of mycophenolate mofetil is more acceptable, as shown by a recent randomized controlled trial [39] and by several observational studies [35,38]. Hematopoietic autologous stem cell transplantation (HSCT) is another possible therapeutic procedure for patients with rapidly progressive JSSc at risk for organ failure and refractory to conventional treatments [40]. HSCT have shown stabilization of lung function in patients with SSc and improvement in event-free survival compared with cyclophosphamide [41,42]. However, considering the potential high risk of treatment-related side-effects, HSCT should be reserved for the treatment of selected patients and be performed in experienced centers [30]. The use of rituximab, a monoclonal chimeric antibody directed against the CD20 antigen on B lymphocytes, may be indicated in severe cases because high levels of B cells have been found in the lung tissue of SSc patients [43]. Open label studies, in adults, showed stabilization or improvement of the lung disease after rituximab treatment [44e47]. Symptomatic treatments are essentially based on the principle of good clinical practice and include proton pump inhibitors (PPI) such as omeprazole and lansoprazole for the prevention of gastroesophageal reflux disease and esophageal ulcers. In asymptomatic patients with SSc, PPI should be used with caution because a long-term therapy might lead to nutritional deficiency owing to reduced intestinal absorption or increased risk of infections [30]. Rotating antibiotics such as metronidazole, ciprofloxacin, and doxycycline are indicated to treat malabsorption due to bacterial overgrowth. Angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, losartan) are effective for the longPlease cite this article in press as: Zulian F, Scleroderma in children, Best Practice & Research Clinical Rheumatology (2018), https://doi.org/10.1016/j.berh.2018.02.004

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term control of blood pressure and stabilization of renal function in case of scleroderma renal crisis [48], while there is no indication as a preventive tool [30]. Low-dose glucocorticoids, preferably prednisone at a dosage of 0.3e0.5 mg/kg per day, should be reserved for the treatment of myositis, arthritis, and tenosynovitis. Because several studies in adults suggest that corticosteroids are associated with a higher risk of scleroderma renal crisis, blood pressure and renal function should be carefully monitored. Course of the disease and prognosis In general, JSSc may have two possible courses: a small group of patients may have a rapid development of multiple internal organ failure leading to severe disability and eventually to death, whereas the majority experience a slow, insidious course with lower mortality risk [16]. The ultimate prognosis for a child with JSSc depends primarily on the extent of visceral involvement. Cardiac arrhythmias may result from myocardial fibrosis, and congestive heart failure is often a terminal event. Pulmonary interstitial disease and vascular lesions are probably universal, even if not clinically evident. Nevertheless, the overall prognosis of SSc in children appears better than in adults. The survival of childhood-onset SSc at 5, 10, and 20 years after diagnosis is 89%, 87.4%, and 82.5%, respectively [16]. Juvenile localized scleroderma JLS includes a group of disorders whose manifestations are confined to the skin and subdermal tissues and, with some exceptions, do not affect internal organs. An epidemiological study in the United Kingdom reported an incidence rate of 3.4 cases per million children per year, the vast majority represented by the linear subtype [4]. The female-to-male ratio of JLS is 2.4:1 and the mean age at onset is approximately 7.3 years [49], although the disease can start as early as at birth as in congenital LS [50]. At this age, a misdiagnosis of skin infection, nevus, or salmon patch may lead to a consistent delay in diagnosis. Classification The forms of JLS are distinguished by the distribution of skin lesions and other associated findings. The most widely used classification includes five subtypes: circumscribed morphea (CM), linear scleroderma, generalized morphea, pansclerotic morphea, and the mixed subtype where a combination of two or more of the previous subtypes is present (Table 4) [51]. Circumscribed morphea is characterized by oval or round circumscribed areas of induration with a central waxy, ivory color surrounded by a violaceous halo (Fig. 5). The superficial variety is usually confined to the dermis. In the deep variety, the entire skin feels thickened, taut, and bound down, as the primary site of involvement is the panniculus or subcutaneous tissue. CM lesions occur most frequently on the trunk and less often on the extremities or face. Generalized morphea is characterized by four or more individual circumscribed lesions, larger than 3 cm, that become confluent and involve at least two of seven anatomical sites (headeneck, right upper extremity, left upper extremity, right lower extremity, left lower extremity, anterior trunk, and posterior trunk). It can be superficial or deep (Fig. 6). Linear scleroderma is the most common subtype in children and adolescents [49]. It is characterized by one or more linear streaks that typically involve the extremities and the trunk. With time, the streaks become progressively more indurate and can extend through the dermis, subcutaneous tissue, and muscle to the underlying bone (Fig. 7). The face or scalp may also be involved, as in the en coup de saber (ECDS) variety. This term was applied historically because the lesion was reminiscent of the depression caused by a sword wound (Fig. 8). The ParryeRomberg syndrome (PRS) is characterized by a progressive hemifacial atrophy of the skin and tissue below the forehead, with mild or absent involvement of the superficial skin. It is considered the severe end of the spectrum of ECDS; therefore, nowadays, ECDS and PRS are better named under the term of linear scleroderma of the face [51,52]. Pansclerotic morphea is an extremely rare but severe disorder characterized by generalized fullthickness involvement of the skin of trunk, extremities, face, and scalp with the sparing of the Please cite this article in press as: Zulian F, Scleroderma in children, Best Practice & Research Clinical Rheumatology (2018), https://doi.org/10.1016/j.berh.2018.02.004

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Table 4 Classification of juvenile localized scleroderma. (adapted from reference no. [50]). Type

Subtype

Features

1) Circumscribed morphea

a. Superficial

Oval or round circumscribed areas of induration limited to the epidermis and dermis, often with altered pigmentation and violaceous, erythematous halo (lilac ring). They can be single or multiple. Oval or round circumscribed deep induration of the skin involving subcutaneous tissue extending to the fascia and underlying muscle. The lesions can be single or multiple. Sometimes the primary site of involvement is in the subcutaneous tissue without involvement of the skin. Linear induration involving the dermis, subcutaneous tissue, and, sometimes, the muscle and underlying bone and affecting the limbs and/or the trunk. En coup de saber (ECDS). Linear induration of the skin that affects the face and/or the scalp and sometimes involves the muscle and underlying bone. Parry Romberg or Progressive Hemifacial Athrophy Loss of tissue on one side of the face that may involve the dermis, subcutaneous tissue, muscle, and bone. The skin is unaffected and mobile. Induration of the skin starting as individual plaques (4 or more and larger than 3 cm) that become confluent and involve at least two anatomic sites Circumferential involvement of limb(s) affecting the skin, subcutaneous tissue, muscle, and bone. The lesion may also involve other areas of the body without internal organ involvement. Combination of two or more of the previous subtypes. The order of the concomitant subtypes, specified in brackets, will follow their predominant representation in the individual patient [i.e., Mixed (linearecircumscribed)].

b. Deep

2) Linear scleroderma

a. Trunk/limbs

b. Head

3) Generalized morphea

4) Panclerotic morphea

5) Mixed morphea

Fig. 5. Circumscribed morphea lesion of the right shoulder characterized by a central area of induration with a waxy, ivory-colored area surrounded by inflammation and hyperpigmentation.

fingertips and toes (Fig. 9) [53]. It is a very disabling condition that may lead to severe limb deformities and even autoamputation due to the fibrotic strictures and occlusions of the deep vascular system. The involvement of the entire body surface without affecting internal organs helps differentiate pansclerotic morphea from SSc. Studies have raised awareness of the possible evolution of chronic ulcers, frequently complicating pansclerotic morphea, to squamous cell carcinoma [54,55]. Please cite this article in press as: Zulian F, Scleroderma in children, Best Practice & Research Clinical Rheumatology (2018), https://doi.org/10.1016/j.berh.2018.02.004

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Fig. 6. Generalized morphea: note the symmetrical disposition of circumscribed skin lesions, with central areas of induration surrounded by halo ring that often become confluent.

Fig. 7. Linear scleroderma of the right foot: taut, shiny, and hyperpigmented skin and shortening of the extensor tendons of the second, third, and fourth fingers with significant functional impairment.

The mixed subtype results from a combination of two or more of the previous subtypes. This subtype accounts for almost one-fifth of the cases [51]. Etiology and pathogenesis The cause and pathogenesis of LS are unknown. Abnormalities of the immune system, regulation of fibroblasts, and production of collagen represent the most important points investigated by Please cite this article in press as: Zulian F, Scleroderma in children, Best Practice & Research Clinical Rheumatology (2018), https://doi.org/10.1016/j.berh.2018.02.004

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Fig. 8. Linear scleroderma en coup de saber affecting the left fronthead and resulting in depression and hyperpigmentation.

experimental studies. Multiple studies have demonstrated increased levels of cytokines and other molecules that influence fibroblasts and collagen synthesis. Autoimmunity, environmental factors, infection, and trauma have all been associated with this localized disease. It seems certain that autoimmunity plays an important role because of the multiplicity of abnormal serum antibodies that occur in patients with JLS along with an increased incidence of autoimmune disorders [56,57]. The most commonly associated diseases include Hashimoto's thyroiditis, vitiligo, and type 1 diabetes mellitus [56e60]. Twelve percent of the relatives of affected patients have an increased incidence of autoimmune diseases [49,60]. However, unlike many rheumatologic conditions, there appears to be no significant increase in risk for JLS among family members. In a large, multicenter review of 750 patients, 13.3% reported specific environmental events as a potential trigger for their disease [49]. These included infections, drugs, mechanical events (accidental trauma, insect bite, and vaccination), and psychological distress. The skin lesion of JLS demonstrates an initial marked inflammatory reaction, followed by matrix deposition, fibrosis, and ultimately atrophy. Because of these histological changes, investigations have focused on the abnormal regulation of collagen production by fibroblasts. Regional susceptibility mechanisms (such as environmental triggers, mosaicism, and others) together with distinct pathogenic determinants (including innate, adaptive, and imbalanced pro- and antifibrotic signaling pathways) are likely implicated. A comprehensive review on this topic has been recently published [61]. Extracutaneous manifestations Almost 20% of the patients with JLS present extracutaneous manifestations [56] that are more frequent in patients with linear scleroderma and consist essentially of arthritis, neurological findings, or other autoimmune conditions. Articular involvement is the most frequent extracutaneous feature

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Fig. 9. Disabling pansclerotic morphea of the right lower limb resulting in extensive, severe involvement of the skin, subcutaneous tissue, muscle, and bone.

(19%) and is more common in patients with linear scleroderma. The joint involved may be completely unrelated to the site of the skin lesion. Children with JLS who develop arthritis often have positive RF [49], and sometimes an elevated erythrocyte sedimentation rate (ESR). The most frequent neurological conditions, reported in linear scleroderma of the face, are seizures and headache, although behavioral changes and learning disabilities have been also described [56,62]. Abnormalities on MRI, such as calcifications, white matter changes, and vascular malformations, have been also reported [63]. Considering that most of these changes have been reported in the linear scleroderma of the face, it is mandatory to perform a MRI of the head in every patient with facial lesions. In these patients, odontostomatologic and ocular abnormalities should be also detected [64,65]. Laboratory findings The diagnosis of LS is established on clinical grounds, as no laboratory abnormality is diagnostic. Routine laboratory tests such as a complete blood cell count, blood chemistries, and urinalysis are usually normal. The acute-phase reactants such as ESR and C-reactive protein (CRP) are usually within the normal ranges with the exception of the deep subtypes in which eosinophilia and hypergammaglobulinemia may be found [49]. RF is present in 25e40% of the patients and is often related to the presence of articular involvement [49]. Autoantibodies are found in many patients with JLS. ANA can be present in any subtype, with a frequency ranging from 23% to 73% [49,66]. Anti-histone antibodies (AHA) have been detected in 47% of patients with LS with a different prevalence in the various subtypesdhigher in generalized morphea and lower in CM [67].

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Anti-topoisomerase I antibodies (anti-Scl 70), a marker of SSc in adults, can be found in 2e3% of children with JLS but not in adults with LS [49,67]. Conversely, ACAs found in 12% of adults with LS have been found only in 1.7% of children [49,68]. aCLs have been found in 46% of adult patients with LS and in 12.6% of young patients [49]. Lupus anticoagulant (LAC) was reported in 24% of the adult patients but never in children. Anti-b2-glycoproteinI (b2GPI) is usually absent [69]. Disease monitoring During the past few years, various methods for the clinical monitoring of JLS have been developed but none has been validated in a large cohort of patients. A semiquantitative scoring method, the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT), consists of the combination of the Skin Severity Index (LoSSI) and the Damage Index (LoSDI) [70]. Although this method does not evaluate the real size of the lesions, it can be performed by physicians in the daily clinical practice without special equipment. A computerized scoring (CSS) method for the measurement of circumscribed lesions allows a more precise evaluation of the extension of each lesion [71]. It involves demarcating the indurate borders of a lesion on an adhesive transparent film, transferring it to a card, scanning, and recording the data in a computer. Calculation of the affected area, performed by computer software, considers the child's growth and therefore allows the monitoring of the lesions over time. Infrared thermography (IT) has been shown to have value in the detection of active LS lesions in children with high sensitivity (92%) but moderate specificity (68%) [72]. The false-positive results are related to the fact that old lesions lead to a marked atrophy of the skin, subcutaneous fat, and muscle, with increased heat conduction from deeper tissues [72,73]. Laser Doppler flowmetry (LDF) is a noninvasive method for the measurement of cutaneous microcirculation of scleroderma lesions [74,75]. LDF detects the increased blood flow of clinically active lesions. It represents a complementary tool in evaluating LS in the sense that while IT can quantitate thermographic changes of visible lesions and even reveal hidden active lesions, LDF can confirm the presence of active lesions and exclude activity in the atrophic ones. High-frequency ultrasound can detect several abnormalities such as increased blood flow related to inflammation, increased echogenicity due to fibrosis, and loss of subcutaneous fat [76,77]. The main limits of this tool are its operator dependency and the lack of standardization. The use of MRI is indicated to evaluate the depth of soft tissue lesions in the deep subtypes of JLS [78,79]. Treatment Over the years, many treatments have been tried for JLS [80]. Management decisions should be based on the particular subtype of disease and on the degree of activity (Fig. 10). CM is generally of cosmetic concern only, and therefore, it should be treated with topical corticosteroids, while other forms of JLS require systemic treatment. Phototherapy with ultraviolet (UV) represents another possible therapeutic choice for LS [81,82]. Limitations for the use of UV phototherapy in children are the need for prolonged maintenance therapy, leading to a high cumulative dosage of irradiation, and the increased risk for potential longterm effects such as skin aging and carcinogenesis [83]. In progressive linear scleroderma and generalized or pansclerotic morphea, systemic treatment, particularly with methotrexate, should be considered. A weekly regimen of methotrexate of 15 mg/ m2 as a single oral or subcutaneous dose is recommended. During the first three months of therapy, a course of corticosteroids such as prednisone should be used as adjunctive “bridge therapy” [84]. A prolonged remission off medication is usually achieved in patients treated for more than 2 years, as 12.5% relapse rate was reported in patients treated for a shorter period [85,86]. Patients who do not respond to this treatment may be treated with mycophenolate mofetil at a dose of 500e1000 mg/ m2 [87]. Although there are, to date, no published trials of biologics or combination treatments,

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Fig. 10. Proposed flowchart for the management of juvenile localized scleroderma.

surveys of clinical practice demonstrate that tacrolimus, cyclophosphamide, and a number of biologics (including TNF or IL6 inhibitors) are being used in some patients for resistant disease [88,89]. Course of the disease and prognosis Unlike SSc, the prognosis with regard to survival for LS is relatively benign. The course is characterized by an early inflammatory phase, with progression to multiple or extensive lesions, then stabilization, and finally improvement with softening of the skin and increased pigmentation around the lesions. In a population-based study of LS, 50% of patients had documented skin softening of 50% or more or had disease resolution by 3.8 years after the diagnosis [90]. A small number of patients had active disease for more than 20 years. One-fourth of the patients with linear scleroderma and 44% of those with deep morphea developed significant disability. Although patients may experience long periods of disease inactivity, studies of adults with childhood-onset disease demonstrate the risk of persistent disease activity. In one study, 56% had permanent damage with 89% having ongoing disease activity as adults [91], whereas in another study, 31% of patients reported active disease and 38% functional limitations after 10 years [92]. This supports the current consensus of early aggressive treatment with systemic therapy unless the disease enters a remission phase.

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Practice points  Juvenile scleroderma has a wide spectrum of disease presentation and severity. Early recognition of the disease allows appropriate treatment and improves the long-term outcome.  In juvenile systemic sclerosis, the presence of Raynaud's phenomenon associated with capillaroscopy changes and positive ANA represents the early triad of the disease that needs to be closely followed.  The introduction of a multidimensional severity score such as the J4S allows a close monitoring of the disease in the clinical practice and represents a useful tool for the treatment decision-making.  It is crucial to select the more appropriate treatment for JSSc on the basis of the type and severity of the internal organ involvement.  Juvenile localized scleroderma should be suspected and classified on the basis of the typical skin manifestations.  The application of clinical and instrumental scoring tools is essential for the definition of the degree of disease activity and remission.  An appropriate, stepwise treatment should be addressed early to avoid permanent functional and esthetic damage.  Systemic treatment with DMARDs such as MTX and/or MMF should be maintained for at least 2 years to ensure a sustained long-term remission.

Research agenda  Prospective validation of outcome measures such as the LoSCAT and the J4S  Evaluation of the efficacy and safety of immunosuppressive drugs such as mycophenolate mofetil and cyclophosphamide and biological agents for the treatment of juvenile scleroderma syndrome  Gain evidence on the efficacy of experimental new antifibrotic agents for juvenile systemic sclerosis

Conflicts of interest The author declares that there is no conflict of interest. No honorarium, grant, or other form of payment was given to prepare the manuscript. Patient consent was obtained where appropriate.

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Please cite this article in press as: Zulian F, Scleroderma in children, Best Practice & Research Clinical Rheumatology (2018), https://doi.org/10.1016/j.berh.2018.02.004