Rudolph's Pediatrics, 22nd Ed.

CHAPTER 206. Scleroderma

Francesco Zulian

Juvenile scleroderma syndromes are multisystem autoimmune rheumatic diseases whose unifying characteristic is the development of hard skin before age 16. They can be separated into two main categories: those with diffuse skin sclerosis involving many sites of the body together with internal organ involvement (juvenile systemic sclerosis [JSSc]) and those with circumscribed skin induration but no vascular or internal organ involvement (juvenile localized scleroderma [JLS]).

JUVENILE SYSTEMIC SCLEROSIS

Juvenile systemic sclerosis (JSSc) is a chronic multisystem connective tissue disease characterized by the symmetrical thickening and hardening of the skin, associated with fibrous changes in such internal organs as the esophagus, intestinal tract, heart, lungs and kidneys, plus arthritis and myositis. A Committee on Classification Criteria for JSSc, including pediatricians, rheumatologists, and dermatologists, recently proposed new classification criteria (Table 206-1).1

EPIDEMIOLOGY

Systemic sclerosis is a rare condition in any age group, with an estimated annual incidence ranging from 0.45 to 1.9 in 100,000, and a prevalence of approximately 15 to 24 in 100,000.2

Onset in childhood is particularly uncommon: children under age 16 account for less than 5% of all cases,3 and fewer than 10% develop systemic sclerosis before age 20.4,5

Table 206-1. Preliminary Classification Criteria for Juvenile Systemic Sclerosis

CLINICAL MANIFESTATIONS

Children developing scleroderma typically present with Raynaud phenomenon and skin changes (eFig. 206.1 ). Raynaud phenomenon is the first sign of the disease in 70% of patients and in 10% it is complicated by digital infarcts (eFig. 206.2 ). It is more common in the fingers but can be observed in other acral regions including the toes, ears, lips, tongue, and tip of the nose.

Proximal skin induration usually develops somewhat later and is the second most common complaint, present in 41% of patients at disease onset.6 Cutaneous changes characteristically evolve in a sequence beginning with edema, followed by induration, and eventually resulting in marked skin tightening and joint contractures. The skin becomes waxy in texture, tight, hard, and bound to subcutaneous structures. This is particularly noticeable in skin of the digits and face where the characteristic expressionless appearance of the skin may be the first clue to the diagnosis (Fig. 206-1).

Other presenting complaints include arthralgia, arthritis, and, although less frequently, muscle weakness, dyspnea, and calcinosis.

In children with juvenile systemic sclerosis, visceral organ involvement may be widespread; when it occurs, it is associated with significant morbidity. The gastrointestinal and cardiopulmonary systems are most commonly involved, but effects on the kidneys, peripheral nerves, and musculoskeletal system also can lead to significant discomfort and disability. Cardiorespiratory complications are the leading cause of death in children with juvenile systemic sclerosis.3,7,8

Gastrointestinal involvement occurs in 30% to 70% of children with juvenile systemic sclerosis. Most affected patients have esophageal dysfunction, resulting in gastroesophageal reflux and dysphagia. Manometry, esophageal scintigraphy, and intraesophageal 24-hour pH monitoring provide more sensitive indicators of diminished lower esophageal sphincter tone and gastroesophageal reflux.9 Large bowel involvement is less frequent and presents as alternating complaints of constipation and diarrhea, bloating or abdominal discomfort.

Pulmonary involvement, although frequently asymptomatic, also may present as a dry, hacking cough or as dyspnea on exertion. Other abnormalities associated with juvenile systemic sclerosis may include pleuritis, abnormal diffusion capacity for carbon monoxide (DLCO) (which may be the earliest manifestation of interstitial fibrosis) or pulmonary arterial hypertension.3,6 Unlike adult scleroderma, juvenile systemic sclerosis is infrequently complicated by pulmonary interstitial fibrosis. High-resolution computed tomography (HRCT) may reveal pulmonary disease even in the presence of a normal chest radiograph. In children, HRCT findings include ground glass opacification, subpleural micronodules, linear opacities, and honeycombing.10 Pulmonary hypertension occurs rarely in pediatric scleroderma.

Cardiac involvement is present in around one fifth of pediatric scleroderma patients and represents a primary cause of morbidity among children with juvenile systemic sclerosis.3,10,11 Pericardial effusions are not common and when present are usually of no hemodynamic significance. Pulmonary hypertension caused by pulmonary vascular disease can lead to myocardial damage and right-heart failure.

In a case series of children with systemic sclerosis, about 10% had some kind of renal involvement including either increased urinary protein excretion or an elevated serum creatinine level.6 Although renal involvement in children appears to be less severe or frequent than in adults, the abrupt onset of accelerated hypertension with acute renal failure (scleroderma renal crisis) remains one of the most severe and dangerous complications of juvenile systemic sclerosis.

FIGURE 206-1. Classical expressionless appearance of a 10-year-old girl with systemic sclerosis. Note also the waxy, translucent appearance of the skin in the upper trunk. (Courtesy of Dr. Ruben Cuttica, Buenos Aires.)

LABORATORY

About one fourth of juvenile systemic sclerosis patients have anemia of chronic disease, or less commonly, macrocytic anemia due to malabsorption of vitamin B12 or folate. Leukocytosis is not prominent but correlates with the degree of visceral or muscle disease. Patients with myositis have elevated levels of a variety of muscle enzymes, including aldolase, lactose dehydrogenase (LDH), and creatine kinase.3,6

High titers of antinuclear antibodies (ANA) are found in up to 80% of children with juvenile systemic sclerosis. The prevalence of both anti-toposomerase I (Scl-70) and anticentromere antibodies (ACA), quite specific for this condition, is lower in children as compared to adults. Thus, 34% of children with juvenile systemic sclerosis test positive for anti-Scl-70, and 7% for ACA, compared to up to 70% and 55% of adult patients, respectively.6

TREATMENT

No controlled trials, and very few reports of any sort, are available to help guide the treatment of juvenile systemic sclerosis.

Nonpharmacologic measures for alleviating symptoms in juvenile systemic sclerosis begin with avoiding cold and trauma, which can exacerbate vasospasm and tissue damage. In addition, physiotherapy can help maintain functional ability, muscle strength, and joint movement while preventing flexion contractures. Corrective splints, especially while patients sleep, are also useful for treating or preventing joint and muscle contractures.

Pharmacologic management of patients with juvenile systemic sclerosis is particularly challenging: No medication has been shown to be of unequivocal benefit in either children or adults with systemic sclerosis. Calcium channel blockers, usually oral nifedipine or nicardipine, are used as first-line therapy for Raynaud phenomenon. Iloprost or other available parenteral pros-tanoids are used to treat more severe systemic sclerosis–related peripheral vascospasm and digital ulcers.8,12 In all cases, these medications must be used with caution in systemic sclerosis because pulmonary or cardiac vessels are not dilated as effectively as peripheral vessels by these agents, and therefore a “steal syndrome” with decreased central blood flow may result. Steroids may be used with care for treating myositis or arthritis, but these may precipitate scleroderma renal crisis.13,14 Pulmonary involvement accompanied by inflammation may be treated with cyclophosphamide, although when interstitial lung disease is purely fibrotic, no therapies are known to be effective.15,16

Low-dose methotrexate has been shown to benefit sclerodermatous skin changes in adults, and therefore are the treatment of choice for skin manifestations in children, especially during the early phase of the disease.17

Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, losartan) are effective for the long-term control of blood pressure and are life saving in cases of scleroderma renal crisis.18 It is not clear whether or not they have a role in preventing this condition.

Proton pump inhibitors (PPI) such as omeprazole and lansoprazole are indicated for the prevention of gastroesophageal reflux disease (GERD) and esophageal ulcers. Prokinetic drugs such as domperidone may be beneficial in the management of symptomatic motility disturbances. Rotating antibiotics, such as metronidazole and doxycycline, are indicated to treat malabsorption owing to bacterial overgrowth.

New drugs for the treatment of pulmonary arterial hypertension, such as bosentan, sitaxentan, and sildenafil, recently have been introduced in adult patients with systemic sclerosis. There is limited experience at present to estimate their risks and benefits in children, but so far the few case reports of their use in juvenile systemic sclerosis suggest that these agents likely have a role in children.

PROGNOSIS

Generally, the prognosis of juvenile systemic sclerosis is poor. Skin tightness and joint contractures inevitably lead to severe disability,19 despite the fact that the skin may eventually soften years after onset of the disease. The most common causes of death in children are related to involvement of the cardiac, renal, and pulmonary systems. Cardiomyopathy, although rare, can be one of the causes of early death, especially in children.20 Interstitial lung disease and renal failure or acute hypertensive encephalopathy supervene as a potentially fatal outcome in few children and seem more likely to occur early in the disease course.7,11

Survivorship has not been determined in any large series of children because of the rarity of this disease and the availability of very few retrospective data. The overall mortality rate at 5 years is around 6% to 15% and is better than that for adults. The causes of death in juvenile systemic sclerosis include cardiac failure (67%), end-stage renal failure (13%), respiratory failure (10%), infections (7%), and hypertensive encephalopathy (3%).7,11

JUVENILE LOCALIZED SCLERODERMA

Juvenile localized scleroderma (JLS), known as morphea, comprises a group of conditions with involvement essentially limited to the skin and subcutaneous tissues. They have various features and range from very small plaques to extensive fibrotic lesions which may cause significant functional and cosmetic deformity.

Although juvenile localized scleroderma is relatively uncommon, it is far more common than systemic sclerosis in childhood, by a ratio of at least 10:1.21 There is a mild female predilection, girls developing the condition about 2.4 times as frequently as boys. Onset is usually during late infancy although a few cases with onset at birth have been described.22

CLINICAL MANIFESTATIONS

Juvenile localized scleroderma can be classified into five subtypes: circumscribed morphea, linear scleroderma, generalized morphea, pansclerotic morphea, and a mixed subtype in which a combination of two or more of the previous subtypes is present (eTable 206.1 ).23-25

Circumscribed morphea (CM) is characterized by oval or round circumscribed areas of induration surrounded by a violaceous halo. It is confined to the dermis with only occasional involvement of the superficial panniculus. Sometimes, as in deep morphea, the entire skin feels thickened, taut, and bound down. By convention, morphea characterized by four or more discrete or coalescent plaques larger than 3 cm is known as generalized morphea (GM) (eFig. 206.3 ).

Linear scleroderma, the most common subtype of morphea in children and adolescents, is characterized by one or more linear streaks that can extend through the dermis, subcutaneous tissue, and muscle to the underlying bone, potentially causing significant deformities (Fig. 206-2). The extremities are typically affected, but face or scalp also may be involved. In such cases the condition is known as the en coup de sabre variety (ECDS), so called because the lesion looks like the depression caused by a sword strike (eFig. 206.4 ). When deeper structures are involved, ECDS may be complicated by abnormalities of the teeth, eyes, or CNS, including calcifications, vasculitis, seizures, or simply nonspecific MRI changes.

FIGURE 206-2. Linear scleroderma involving the whole right lower limb and resulting in undergrowth of the foot and hyperpigmented skin.

Pansclerotic morphea, an extremely rare but severe subtype, is characterized by generalized full-thickness involvement of the skin of the trunk, extremities, face, and scalp with sparing of the fingertips and toes.

Children with morphea may present with extracutaneous involvement, such as arthritis (19%) neurological abnormalities (4%), autoimmune conditions (eg, thyroiditis) (3%), Raynaud phenomenon or deep vein thrombosis (2%), or ocular and gastrointestinal abnormalities (2%).26 The most frequent neurological complications are seizures and headaches, although behavioural changes and learning disabilities also have been described.

LABORATORY

In a large cohort of patients, antinuclear antibodies (ANA) were found in 42%, rheumatoid factor in 16%, and antiphospholipid antibody in 13% of patients but there is no correlation between their presence and a particular subtype or disease course (eTable 206.2 ).

TREATMENT

The management of juvenile localized scleroderma is challenging and the detection of disease activity and progression remains a fundamental problem.

Infrared thermography (IRT) has been shown to be of value in the detection of active lesions.26 A computerized skin score (CSS) for the measurement of circumscribed lesions in juvenile localized scleroderma has been proposed recently.27 MRI is also an important tool in the clinical management of juvenile localized scleroderma, especially when CNS or eye involvement is suspected. This technique is able to demonstrate the true depth of soft tissue lesions and the degree to which various tissues are involved.

Over the years, many treatments have been trialed for localized scleroderma. Unfortunately, the rarity of this disease and the difficulty of reproducibly assessing outcomes have limited the interpretation of most of these studies. Circumscribed morphea generally is of cosmetic concern only, and lesions spontaneously remit with residual pigmentation as the only abnormality. Treatment should be directed mainly at topical therapies such as moisturizing agents, topical glucocorticoids or calcipotriene.27 Phototherapy with ultraviolet wavelengths (UV) represents another possible therapeutic choice. However, the increased risk for premature aging of the skin or carcinogenesis limits the use of phototherapy in pediatric patients.

When deeper or larger lesions threaten severe cosmetic or functional sequelae, systemic treatment with methotrexate in combination with corticosteroids should be considered.28,29 Although studies promoting this approach are generally small and uncontrolled, in most series patients show a response within 2 to 4 months, and the side effects are usually mild and associated more with steroids than with the methotrexate.