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Scleroderma in children

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Abstract

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.

Section snippets

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

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 10–20 years account for only 1.2–9% 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

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

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]

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

Autoantibodies

High-titer ANA is frequently present (81–97%) 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 28–34% 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.

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 occur very often [20]. Echocardiographic

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

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.

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

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

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 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

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 (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

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 25–40% of the patients and is often related to the

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

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

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

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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      The assessment and monitoring of disease activity and severity are therefore crucial. Although several objective clinical scoring methods have been proposed in recent years, many lack specificity and have not been validated in a large cohort of patients (Zulian 2017). Of the available measures, the LS Cutaneous Assessment Tool (LoSCAT) has the most supportive evidence, having shown excellent reliability in prior LS studies (Arkachaisri and Pino 2008; Arkachaisri et al. 2009; Arkachaisri et al. 2010; Kelsey and Torok 2013; Agazzi et al. 2018; Li et al. 2018).

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