Localized scleroderma in children: clinical, diagnostic and therapeutic aspects

Abstracts

A esclerodermia localizada, ou morféia, acomete crianças em idade escolar e, em geral, é autolimitada, apesar de localmente desfiguradora. A literatura descreve inúmeros fatores etiopatogênicos, bem como modalidades de investigação e tratamento. Este artigo reúne os estudos mais recentes e discute sua aplicação clínica.

Criança; Esclerodermia localizada; Revisão

REVIEW ARTICLE

Localized scleroderma in children: clinical, diagnostic and therapeutic aspects

Pedro C. Q. Zancanaro^I; Adriana R. Isaac^II; Luisimara T. Garcia^III; Izelda M. C. Costa^IV

^I3rd Year Resident Physician, Service of Dermatology, Hospital Universitario de Brasilia (HUB/UnB), Brasilia, Brazil

II2nd Year Resident Physician, Service of Dermatology, Hospital Universitario de Brasilia (HUB/UnB), Brasilia, Brazil

IIIFormer Resident Physician, Service of Dermatology, Hospital Universitario de Brasilia (HUB/UnB), Brasilia, Brazil

IVCoordinator, Dermatology Residence Program, Hospital Universitario de Brasilia (HUB/UnB), Brasilia, Brazil

Mailing Address

ABSTRACT

Localized scleroderma or morphea affects school-aged children, is usually self-limited and a disfiguring condition. Several etiopathogenic factors, investigations and treatment options are described. This article reviews the recent literature and discusses its clinical applications.

Keywords: Child; Childhood; Review; Scleroderma, Localized

INTRODUCTION

Scleroderma is a word used to describe a spectrum of conditions characterized by hardening and/or thickening of the skin and fibrosis of the tissues involved; it is, didactically, divided into systemic and localized forms^1,2 The localized form, also known as morphea, is characterized by predominant skin involvement, with occasional involvement of subjacent muscles, usually sparing internal organs^1,2.

BACKGROUND

The areas of hardened skin were first described, by Addison, in 1854, who called them keloids. The word morphea was introduced by Wilson. In 1868, Fagee differentiated it from keloids and described different forms of localized scleroderma, including the variant en coup de sabre. ¹ In 1942, Klemper et al. added scleroderma to the group of collagen diseases.

Epidemiology

Localized scleroderma is a rare disorder. The largest population-based study was carried out by Petersen et al. ^3,4 and assessed the prevalence and the incidence of morphea and its subtypes in Minnesota, during a 33-year period (1960 to 1993). Eighty-two cases were identified and the annual incidence was determined as 2.7 cases per 100,000 inhabitants. Except for the linear subtype, in which there is no sex predominance, the male:female ratio was 2.6:1. The mean age upon diagnosis was 30 years (range from 1 to 82 years) and in the group with the linear form, it was 18 years. There was no severe involvement of internal organs or progression to the systemic form of scleroderma in any of the cases. Arthritis, synovitis, uveitis and joint contractures were more frequent in the linear scleroderma and deep involvement categories. Deformities leading to physical disability occurred in 11% of patients, 44% of them in the group with deep involvement. The survival rate was similar to that of the general population. ^3,4

Etiology

The cause of scleroderma is unknown. The association with trauma, viral (Epstein-Barr) and bacterial (Borrelia burgdorferi) infections, vaccination and auto-immune diseases was reported. The finding of spirochetes in morphea lesions, during the 1980s, raised the possibility that B. burgdorferi was an etiologic agent, ^5,6 but new studies did not confirm this association^7,8. The lesions of localized scleroderma were observed after immunization with BCG and triple viral, ⁹ surgical procedures, varicella and local trauma. After these observations, it was hypothesized that different aggressions could release inflammatory mediators and cytokines, inducing fibrosis. ² The auto-immune nature of this disease is suggested by the presence of auto-antibodies and auto-immune disorders in patients and their families, by the deposit of immunoglobulins and complement (C3) in histological examinations and by the occurrence of morphea in the chronic phase of the graft versus host disease.

Pathogenesis

As in other auto-immune diseases, it is postulated that an environmental factor in a genetically predisposed individual activates the immune system with the release of cytokines, fibroblast proliferation, collagen synthesis and fibrosis. Although morphea and systemic scleroderma are different conditions, they probably represent parts of the same pathological process, with three basic disturbances ^2,10,11 identified in the pathogenesis: vascular injury, disturbed immunoregulation and disturbed collagen metabolism. There is perivascular infiltration and endothelial cell injury in the initial stages of localized scleroderma. Increased serum levels of the adhesion molecule found in blood vessels - VCAM-1 (vascular cell adhesion molecule-1) - and of E-selectin (receptors found in vascular cells mediating initial adhesion between intravascular leukocytes and the endothelium) are evidence of vascular injury by the inflammatory cells.¹² Lesion and intact skin biopsies showed a thickened vascular wall infiltrated by macrophages and mast cells.¹³ Complement regulating molecules of endothelial cells are less abundant, leaving the endothelium susceptible to the action of the autologous complement with consequent endothelial injury.² Vascular injury seems to cause the release of cytokines and the exposure of the subendothelium to the circulating platelets, causing the deposit of fibrin and eventual formation of intravascular thrombi.¹⁰ Histology and immunohistochemistry suggest that skin fibrosis in scleroderma begins around the capillary vessels in the reticular dermis, next to the fat cells and subcutaneous tissue.¹⁴

There are several immunological disturbances in scleroderma. There is evidence suggesting that chronic persistent inflammation plays a major role in the pathogenesis of morphea. It was demonstrated that the extent of the lymphocytic infiltrate correlates with severity and prognosis of the skin sclerosis.¹⁵ The CD4+ T-lymphocytes predominate in mononuclear cell skin infiltrates. T-lymphocyte activation is shown by increased levels of the interleukins IL-2, IL-4, IL-6 and the IL-2 receptor.9 The expansion of these inflammatory cells in affected tissues release cytokines and growth factors that initiate and/or perpetuate the process of fibrosis and vascular injury. One of the growth factors seemingly involved in the fibrosis process of the sclerosis is the transforming growth factor beta (TGF- β). Small amounts of TGF-β act on fibroblasts, sensitizing and keeping them activated by means of autocrine signaling, which stimulate, along with other processes, additional synthesis of TGF-β. ^16,17

In addition to the activation of T-lymphocytes, B-lymphocyte alterations also play an important role in the pathogenesis of morphea. ^1,2 The presence of antinuclear antibodies (ANA) and of rheumatoid factor (RF) are also associated to B-lymphocyte dysfunction.

One study demonstrated that the perivascular fibroblasts of scleroderma had increased messenger RNA for collagen synthesis.¹⁸ There is also increased synthesis of fibronectin and glucosaminoglycans by fibroblasts. In morphea lesions there was increased type I, II, IV collagens.¹⁹ Fibroblast activity is disturbed because of their interaction with the inflammatory cells and cytokines they release. IL-1 and IL-4 stimulate fibroblast proliferation and the synthesis of collagen, while IL-6 stimulates matrix metalloprotein synthesis.15 In addition, Lê Roy 20, and later, Jimenez et al. ¹⁶ observed that fibroblasts removed from skin affected by scleroderma lesions show in vitro overproduction of collagen and extracellular matrix components, suggesting that these cells might have an impaired biosynthetic pattern.

Histopathology

Scleroderma is histologically characterized by fibrosis and thickening of collagen fibers. ²

In the early inflammatory phase,^1,21 especially in the active lilac ring of the lesions, the reticular dermis collagen bundles are thickened and there is, predominantly, lymphocytic interstitial and perivascular inflammatory infiltrate. It may involve the subcutaneous fat, with trabecular thickening and replacement by neoformed collagen. In the late sclerotic phase, as seen in the core of the lesions, the inflammatory infiltrate is reduced. The reticular dermis collagen bundles become thickened, clustered, hypocellular and hypereosinophilic. In the papillary dermis, normal fibers can be replaced by homogeneous collagen. Blood vessels are rare within sclerotic collagen, their lumen is often narrow and their walls, fibrotic.^1,21 The exocrine glands are atrophic, with few adipocytes around them and surrounded by neoformed collagen. There are no hair follicles or sebaceous glands.

In linear, segmental, subcutaneous and generalized morphea, the underlying fascia and striated muscles may be affected with vacuolated muscle fibers, separated from each other by edema and focal collections of inflammatory cells.²¹

The epidermis, although it may become atrophic, is usually normal, even in old lesions. IgM and C3 perivascular and basal membrane deposits are described in the linear variant of localized scleroderma.

Clinical Manifestations

Localized scleroderma may range from small plaques to extensive disease with cosmetic and functional deformities.²² Atrophy of the underlying structures may, rarely, be observed. ¹⁹ Morphea is ten-fold more common than systemic sclerosis, is usually found in school age children, and it is rare between the ages of 20 and 50 years. ²²

It is, usually, self-limited, with variable outcomes depending on the clinical aspects: faster in the linear form in limbs, and gradual in the plaque form. The prognosis is good: the superficial forms improve, in average, after three years. ^23,24

Clinically, it is subdivided into five types: in plaques, linear, en coup de sabre, generalized and pansclerotic. After the initial erythema, a raised or depressed yellow whitish plaque will be formed, surrounded by blue-purplish erythema (lilac ring ). As skin infiltration occurs, atrophy becomes apparent with loss of hair and sebaceous glands and hyper- or hypopigmentation.

1) Morphea in plaques or circumscribed

This is the most frequent clinical presentation in the general population.²³ It encompasses two subtypes: superficial and deep. It usually occurs on the trunk, involving especially the area over the iliac crests.

In this clinical form, the plaque with the lilac ring evolves into a hairless and anhydrotic ivory infiltrate.²⁵ The end result are oval or round circumscribed, hardened, infiltrated plaques, with ill-defined borders, measuring 2 to 15 cm in diameter. The lesions are rather palpable than visible. The lilac ring may be evident months or years later.¹⁹

The lesion may extend more often towards the thorax, abdomen, buttocks and lower limbs. Face, neck and upper limbs involvement is rare. ²³ (Figure 1)

Morphea guttata is the name used to describe multiple sclerotic hypopigmented lesions, which may represent disseminated morphea and must be differentiated from lichen sclerosus and atrophicus.^23,26 The coexistence of such disorders has already been described.²⁷

Subcutaneous morphea is found on the upper trunk, upper and lower limbs, it may be unilateral or circular on thighs and buttocks. Deep dermis and subcutaneous layers are involved, and the skin resembles peau d'orange and sometimes displays ulceration. The skin becomes stiff and there may be joint contractures and arthralgia.²⁸

2) Linear morphea of the limbs and trunk

Linear scleroderma is the most common subtype in children and adolescents, especially in school age girls. Clinically, linear bands of sclerosis which may extend to the dermis, subcutaneous tissue, muscle and bones, causing deformities.²² (Figure 2) It is uncommonly bilateral. Although rare, it may involve the face, upper limbs and leg unilaterally – hemiatrophy.^23,29

3) Linear morphea of the face, en coup de sabre

It is usually unilateral in the face (frontoparietal or hemi-facial), with a central marking line. After a brief phase of erythema and edema, sclerosis and atrophy ensue, with local depression.25 After skin involvement, the underlying tissues are affected, and hemiatrophy of the face may occur.

The scleroderma en coup de sabre is particular in tha

t it has central nervous system (with seizures, headache, hemiparesis or focal symptoms), eyes (uveitis or vasculitis) or mandible (misalignment and dental problems) involvement.^{30, 31, 32, 33} Imaging (MRI, SPECT) shows atrophy or cortical calcification. The spinal fluid analysis is consistent with intracerebral inflammation.^34,35 (Figure 3)

In Parry-Romberg facial hemiatrophy there is bone, muscle and subcutaneous tissue changes, with or without skin sclerosis. It may coexist with en coup de sabre morphea and its nosologic position is still debatable. Whether it is a part of the spectrum of facial linear scleroderma or a separate entity, it shows similar neuro-ophthalmologic changes^35,36

The occurrence of epilepsy is related to the presence of brain lesion underlying the sclerosis. Imaging and histopathologic studies showed focal inflammatory processes, most of the time, progressive.³⁷

4) Generalized morphea

It is a rare condition, it occurs in the cases of disseminated sclerosis with no systemic involvement. It occurs mainly in adults and it is diagnosed when four or more plaques become larger than 3cm and merge, involving two of the seven main anatomical areas (head and neck, left or right upper limb or lower limb, anterior or posterior trunk).²² It begins in the trunk and causes contractures and deformities in the limbs. It differentiates from systemic sclerosis because it does not accompany Raynauld's phenomenon and does not show capillaroscopic changes.^22,23 Chronic graft versus host disease may cause generalized morphea.

5) Pansclerotic morphea

It is an extremely rare, severe, generalized disease characterized by involvement of total skin thickness. Joint involvement causes pain and edema. Commonly, limb contracture and retraction are observed. Chronic ulceration was described associated to squamous cell carcinoma. ^{35,38,39,40,41} (Figure 4)

Combined forms: the coexistence of different forms may occur, and this is more often seen in children, with the linear and in plaque forms. Combination of trunk plaque lesions and linear ones on the limbs or en coup de sabre on the face are also encountered. Overlapping clinical forms support common pathophysiology. Other combined forms include morphea and lichen sclerosus and atrophicus, as well as morphea and atrophoderma of Pasini and Pierini.²³

Other findings: usually circumscribed to the skin and subcutaneous tissue, morphea does not involve the internal organs, even in severe forms. The disease in children is sometimes associated to systemic symptoms including arthralgia, Raynauld-like symptoms, abdominal cramps, gastroesophageal reflux, neurological symptoms, disturbed heart conductivity, pericarditis and non-specific muscle pain. ¹⁹ These symptoms are usually mild or non-existent, more common in deeper cutaneous forms.

Morphea has been described in association to vilitigo, lichen planus, alopecia areata and collagen diseases, such as systemic lupus erythematosus (SLE), dermatomyositis and rheumatoid arthritis. ⁴² (Figure 5)

Laboratory Abnormalities

There are several laboratory abnormalities in morphea. Eosinophilia may be found in patients with linear or generalized scleroderma and is often associated with the extent of the disease. Hypergamaglobulinemia with elevated polyclonal IgM and IgG occurs in almost 50% of patients with severe skin disease and is more common during clinical progression.⁴³

An international study involving 750 cases of juvenile localized scleroderma,44 revealed the increase in acute phase reactants, especially in cases of deep morphea. In the linear form, the erythrocyte sedimentation rate (ESR) was high in 22.2% of cases.

Several auto-antibodies are found in morphea,^45,46 and the high titers correlate with disease severity, including antinuclear antibodies (46-80%), anti-ssDNA (50%) and antihistone (47%).

The frequency of present antinuclear antibodies (ANA) in children with morphea differs among studies, ranging from 23% to 63%. It occurs more often in patients with generalized morphea, followed by linear scleroderma and localized morphea.⁴⁷ High levels of single helix anti-DNA antibodies (anti-ssDNA) were found in localized scleroderma. Patients who had muscle involvement had higher levels of these antibodies than patients with no muscle involvement. The titers of anti-ssDNA are well correlated with disease activity. Falanga et al. reported that anti-ssDNA antibodies were frequent in generalized morphea.⁴⁸ Anti-ss-DNA antibodies were associated with joint contractures, deformities or more extensive, active and long-standing disease.⁴⁷

In another study, anti-histone antibodies were demonstrated using ELISA, in 47% of patients with localized morphea and 87% of those with generalized morphea. The presence of anti-histone antibodies was highly correlated with the number of morphea lesions and the number of body areas affected. For generalized morphea, sensitivity is 87% and specificity, 74%.48

Anticardiolipin antibodies were found in 46% of patients with localized scleroderma and of those, 67% had generalized morphea and 35% had linear morphea. In the generalized form, the frequency of IgM anticardiodiolipin antibodies (61%) was much higher than that of IgG antibodies (28%).⁴⁸

Rheumatoid factor (RF) may be found in 39% of patients⁴³ and is significantly correlated to the presence of arthritis.44 In juvenile localized scleroderma, RF was found in 16% of patients, showing significant correlation with the presence of arthritis. In adults, its IgM form is present in up to 60% of patients and seems to correlate with severity of the disease.^45,46,48,49

More specific auto-antibodies, such as Scl-70, anti-centromere, Ro/La and U1RNP may precede systemic disease, and patients who show these markers must be followed up for several years.50 Patients with anti-Scl 70 and anti-centromere antibodies showed signs or symptoms of organic involvement after a three-to-four-year follow-up. It is still unknown whether such antibodies are markers and show the immunologic component of the disease, or if they have a prognostic significance.⁴⁴

The serum levels of tumor necrosis factor alpha (TNF-a) and interleukin 13 (IL-13), major fibrosis stimulators, are significantly high in patients with localized scleroderma compared to healthy subjects.⁴⁵

Imaging

The activity of a linear scleroderma lesion is often assessed by thermography. ^47,51 This technique may detect temperature increase in active areas and areas of new lesions. ⁵² A morphea lesion is considered as thermographically active if its temperature differs by + 0.5°C from the adjacent area or from the contralateral limb.⁵³

Martini et al. compared the thermographic assessment with the clinical description of lesions and showed that thermography had 92% sensitivity and 68% specificity.⁵¹ It is a promising diagnostic method when associated to the clinical assessment to determine disease activity, if applied to lesions with no severe atrophy.^1,51,54

Radiological studies, especially, magnetic resonance imaging (MRI) are effective ways to visualize structural abnormalities and to document the progression of connective tissue atrophy and bone changes; they are especially useful in the linear and en coup de sabre forms. In a review of radiological findings in 23 patients, of the five with lower limb involvement, they all had discrepant leg length, deformity of bone remodeling and atrophy of subcutaneous fat and the adjacent muscles. MRI is useful when there is ocular or central nervous system (CNS) involvement suspected.^45,50,55

High frequency ultrasound (US) informs on the skin anatomy, showing details of the dermis and subcutaneous layers.53 The 20MHz US allows determining the depth and extent of sclerosis in the affected area.56 In pediatric patients, it may show the loss of subcutaneous fat and muscle, increased blood flow and increased ecogenicity due to collagen condensation in the dermis. Hyperemia and the increasing ecogenicity seem to point to active lesions.57 Two major limitations of this method are an operator-dependent assessment and the lack of validation as outcome measures in prospective studies.^45,57

Other techniques which may potentially inform about the disease are either laser Doppler flowmetry or laser Doppler imaging.⁵³ A recent study in 41 children showed that blood flow measured by these techniques was significantly increased in the clinically active lesions of localized scleroderma. Sensitivity was 80% and specificity, 77%, for the detection of active lesions, in cases of, at least, 39% increase in blood flow.⁵⁸

Prognosis

Regarding progression to systemic involvement, the prognosis of morphea is usually good. It rarely evolves to systemic scleroderma (0.9 to 5.7% of cohorts). Morphea lesions rarely coexist with other systemic auto-immune diseases, such as dermatomyositis, polymyositis, SLE, primary biliary cirrhosis, rheumatoid arthritis and mixed connective tissue disease.⁴⁶46

Although the prognosis of localized scleroderma is good, it may involve not only skin, but also the subcutaneous tissue, muscles, bone and synovia, causing deformity and dysfunction.⁵⁹ Some children will have spontaneous and complete remissions, even when the disease had a severe start, others will show progression to debilitating or fatal outcome.⁵⁵

Plaque, isolated, disseminated and gutata are morphea types which usually have moderate and self-limiting courses. Clinical activity lasts usually for three to four months.^46,53

Approximately, 20% of patients with localized scleroderma in the lower limbs develop significant atrophy of the adjacent tissues, with a possible outcome of length discrepancy of 1.5 to 7 cm. Immediate treatment is mandatory.⁵⁹ The limb may become contracted in severe cases and significant leg deformity may ensue in children who underwent a long inflammatory phase, as seen in the patient of Figure 2.⁵³

The en coup de saber type may evolve with bone atrophy, mandibular deformity, abnormal positioning of the teeth and aesthetic damage due to hemiatrophy or cranial and CNS deformity. ⁵³

Unfortunately, pediatric patients are under greater risk of long term morbidity, due to changes secondary to growth because of bone involvement, face and limbs asymmetries, psychological derangement and physical disability.^50,60

Differential Diagnosis

Some clinical syndromes must be considered. These include changes in nails and digital flexures associated to endocrine conditions (diabetes and thyroid diseases), inborn errors of the metabolism, such as mucolipidoses and phenylketonuria, post-infectious scleroderma and arthropathies⁵⁵.

The differentiation with systemic scleroderma is not difficult in plaque morphea, but it may become a problem in generalized and linear morphea. In these cases, it may be necessary to perform more studies. Raynaud phenomenon and the involvement of the internal organs are the most common findings that one should look for in order to differentiate from systemic scleroderma. Sclerodactily and nail pitting are rare in localized forms. Deep forms of morphea may be difficult to be differentiated from lupic panniculitis and other panniculites. Histological and immunopathological studies may be necessary for this differentiation.⁶¹

Early stage plaque morphea must be differentiated from annular erythema, erythema migrans and scleroderma. Lesions resembling sarcoidosis were also described. Single atrophic lesions of the plaque variant may look similar to atrophoderma after intramuscular injection of corticosteroids and vitamin K. The guttata type resembles lichen sclerosus and atrophic; however, histological differences help in the differentiation. Facial hemiatrophy caused by en coup de sabre variant is difficult to differentiate from progressive hemifacial atrophy with no sclerodermic lesions, known as the Parry-Romberg disease. It is not known if it is a distinct disease or a variant of linear scleroderma, but it is agreed by many that their similar forms are related to craniofacial scleroderma.^50,53

Linear scleroderma in the extremities in children must be differentiated from eosinophilic fasciitis (Shulman syndrome). However, this is a very rare occurrence in childhood.⁵³

Treatment

Because of its unknown etiology, no specific treatment for the disease is available. Some topical and systemic medications, added to physiotherapy may be effective in limiting disease progression.⁵³ The goal of the therapy is to curtail disease progression early, in order to prevent functional and cosmetic complications.^1,54 Therapeutic choices must be made after assessing the extent and severity of the disease, the rate of progression as well as a discussion about potential risks and benefits of the therapeutic options with parents and children.⁵⁵

The drugs used are generally aimed to suppress inflammation and collagen changes. Several treatments, such as penicillamine, anti-malarial agents, retinoids, calcitriol, calcipotriol, imiquimod, cyclosporine, interferon and UVA radiation have been used to treat localized scleroderma with variable rates of success and frequent small effects in the linear and deep forms. Corticosteroids and methotrexate in small doses have been repeatedly reported as beneficial for linear scleroderma and in children, methotrexate has been the most frequently used treatment in the past five years.^1,44

Sometimes, encouraging results with potent topical corticosteroids are obtained in early disease phases, especially, in plaque morphea. ^47,53 In single plaque lesions, patients must be informed of the benign and often self-limited character of the disease. Topical or occlusive steroids may be used to enhance absorption. Intralesion triamcinolone showed to reduce progression when injected in the lesion margins. However, this increases the risk of inducing necrosis or lipoatrophy. Daily hydration is beneficial. In pruriginous regions, topical capsaicin may be used.⁵⁶

When the lesion grows rapidly or functionally involves important areas, systemic therapies must be indicated. In these cases, oral corticosteroids are the first choice. The indications for oral steroids in localized scleroderma are: a) exuberant clinical inflammatory findings with rapid progression of the lesion, b) functional damage or suspicion of functional damage, c) possible growth disturbance, d) muscular lesion and high anti-ss DNA antibodies levels.⁴⁷

Weibel et al. published the largest retrospective series of children with localized scleroderma treated with corticosteroids and methotrexate (MTX). All patients improved significantly with the therapy and none quit treatment due to adverse effects.¹

In practice: induction therapy with methylprednisolone 30mg/kg/day (maximum dose 500mg/day) given in daily infusion for three days and repeated for three more days the following week. Oral prednisone is initiated after the first methylprednisolone course, in the initial dose of 0.5 to 1.0 mg/kg/day, for at least four weeks, and gradually reduced thereafter for a total period of three to six months. Maintenance treatment is done with methotrexate, starting it after the second methylprednisolone pulse. The initial dose is 10mg/m2/week and it may be given by mouth or subcutaneously. When the disease activity is controlled, the dose may be reduced but the drug must be continued for at least one year after the disease is inactive.53 Maintenance treatment must be continued for one to three years and the patients must be followed regularly after the end of the treatment for, at least, five years. It is suggested that monitoring with blood tests (complete blood count, electrolytes, urea, creatinine, liver function test, especially alanine transaminase - ALT), weight and height and, while in use of corticosteroids, blood pressure monitoring and urinalysis, every four to six weeks, should be done throughout the treatment., ^{53, 54, 55}

Uziel et al. believe that corticosteroids are induction agents, which reduce the inflammatory component of the disease and that methotrexate acts on chronic inflammation and fibrosis.62 The mechanism by which low dose MTX is able to improve skin fibrosis remains little understood. It may act directly on fibroblasts or skin improvement is due to its anti-inflammatory effect.^1,54 It acts, probably, through the inhibition of several cytokines (IL 2, 4, 6 and 8), which are increased in localized scleroderma and are correlated with the degree of cutaneous sclerosis.⁶³

Cyclosporine is a fungus metabolite with potent immunosuppressant activity affecting both cell and humoral immunity. It has been effective in the treatment of systemic scleroderma as well as of disabling morphea. Several authors showed response to cyclosporine in their patients, more evident in skin lesions than in systemic involvement. Cyclosporine selectively inhibits the release of IL-2 from activated lymphocytes. The clinical benefit of its use in systemic sclerosis was underestimated because of its side effects, especially renal damage and hypertension, probably due to the use of high doses, above those used for skin disease. Cyclosporine is, currently, considered well tolerated by children if properly monitored, and it may be an important tool in therapy due to its fast initiation of action.⁵⁹

The presence of cutaneous receptors for calcitriol suggests that the skin is not only the organ producing this hormone, but the target organ for its action as well. Calcitriol has different actions on scleroderma, such as: immunomodulatory effects on lymphocyte and monocyte/macrophage functions, dose-dependent inhibition of fibroblast proliferation, direct effect in the regulation of the expression of the collagen gene. Elst et al. ⁶⁴ showed, although in a small number of patients (7 children), that systemic calcitriol may be an effective therapeutic agent for localized scleroderma in childhood. Improvements in skin rigidity and joint mobility was observed in six children after three months of treatment. It is suggested that calcitriol must be given for at least three months in children with linear scleroderma before introducing more aggressive therapy. If improvement is observed, the treatment should be maintained for six to nine months.^64,65

In a study with 12 patients aged 12 to 38 years, with active morphea or linear scleroderma, histologically confirmed, calcipotriene 0.005% lotion was applied on the plaques with occlusion, twice a day for three months, with significant improvement and no side effects.⁶⁶

Since the mid 1990s, phototherapy with UV radiation has been used to treat patients with localized scleroderma and exclusive cutaneous involvement. Studies using UVA 1 treatment in small, intermediate and high doses with or without psoralens (PUVA) showed beneficial clinical effects, although the high doses seem to be more effective. The number of weekly sessions varied from three to five and the total number of sessions, from 20 to 40. Different mechanisms of action explain how UV phototherapy may act, including the increase in matrix collagenase-metaloproteinase-1 activity, increase in the expression of IFN-γ and reductions of TGF-β. Despite its relative safety, there are concerns regarding malignancies, especially in children. ⁴⁵

Kreuter et al., in a controlled, randomized clinical trial, compared UVA1 radiation in small and intermediate doses and narrow-band UVB in 64 patients with localized scleroderma restricted to the skin and subcutaneous tissue. The treatment was given five times a week during eight weeks. Each treatment type was effective, although UVA1 in intermediate doses was statistically better than UVB. There was significant histological improvement in the treatment with UVB. Ultrasound showed reduction in skin thickness and increase in dermis density only in intermediate dose UVA1.⁶⁷

Collagenase production by UVA is dose dependent and directly related to the amount of UVA higher than 60 J/cm2. However, satisfactory response was found with low doses (20 J/ cm2) early in treatment. The results of El-Mofty et al. showed satisfactory clinical response at low UVA doses (5, 10 and 20 J/cm2/session), in a total of 20 sessions.⁶⁸

This same investigator took part in another study to demonstrate the efficacy of low dose UVA, in which 12 patients with morphea were exposed to UVA 20 J/cm2 three times a week, during 20 sessions. Some plaque lesions were covered in order to act as controls. The efficacy of the therapy was determined clinically and by biopsy samples. Softening of the lesions was seen in all patients, confirmed at the examination. A significant reduction in the mean collagen concentration was found in the plaques exposed to UVA, while in the covered plaques the difference was not statistically significant. The authors concluded that UVA phototherapy in small doses is a quite effective and safe therapeutic modality for localized scleroderma. ⁶⁹

Photochemotherapy using psoralenes and UVA (PUVA) causes apoptosis of the T cells infiltrating the skin and for many years has been shown to have highly beneficial effect on some disorders, such as psoriasis, atopic dermatitis and T-cell cutaneous lymphoma. Although no control studies have been published, excellent results were reported with the PUVA treatment in patients with localized scleroderma.⁷⁰

Pasic et al. reported the treatment of six children with localized scleroderma with photochemotherapy with PUVA baths, with good results concerning softening of sclerotic plaques. The results were obtained with a small number of sessions (average of 25, ranging from 14 to 39).71 After UVA radiation, an increased expression of collagenase may be detected in dermis fibroblasts. It is speculated that UVA radiation may suppress the synthesis of collagen and induce collagenase activity, with resulting clinical improvement of the sclerotic plaques. ⁷²

Grundmann et al. showed that topical treatment with PUVA induced significant improvement in four patients treated time times a week, totaling up 30 sessions. The improvement was clinically, ultrasonographically and histopathologically demonstrated.⁷³

In a clinical trial involving seven patients for three months, lesions treated with occlusive topical tacrolimus for 12 hours at night, presented softened and reduced inflammatory erythema in all patients one month after treatment. However, double-blind control studies are necessary to confirm its use. The mechanism by which tacrolimus induces scleroderma lesion regression is not clear. It probably has an immunomodulating and anti-inflammatory effect related to the inhibition of T-lymphocyte activity and reduction in production of inflammatory cytokines. ⁷⁴

Imiquimod is an imunomodulator that interferes in the action of several cytokines, including IFN-α and γ, capable of inhibiting collagen production in fibroblasts.45 Dytoc et al. reported a series of 12 patients with the histological diagnosis of morphea, treated with imiquimod, initially three times a week, followed by daily use. Eleven of 12 patients showed a 29-60% improvement in three months, and seven of 12 patients had a 38-100% improvement in six months. Histology showed 4-33% improvement regarding skin thickness, in four patients. Side effects were minimal and restricted to local irritation, which regressed by lowering the frequency of use of the drug. However this was an uncontrolled study and more investigation is needed to corroborate this benefit.⁷⁵

Kreuter et al., as well as Christen-Zaech et al. , concluded that combined therapy with MTX and corticosteroids should be considered as first line treatment of severe localized scleroderma, which also affects some extracutaneous structures, such as fat, muscle, fascia and/or bones. However, patients with plaque morphea, which generally affects only the dermis, do not benefit as much with this therapeutic option, especially taking into account their potential side effects. These patients usually respond well to the local treatment with corticosteroids, vitamin D3 analogs and/or phototherapy. PUVA therapy should be considered in the early stages of inflammation, while phototherapy with UVA1 is more beneficial in the fibrotic stages of morphea.^76,77

Regular physiotherapy is essential, especially in the cases of linear morphea, in order to prevent the appearance of contractures. For children with leg shortening, orthopedic surgery may be necessary.^52,53

If a child has a moderate and probably self-limited disease, as small plaques of linear scleroderma not involving the joints, he/she should be watched with no medical intervention, physiotherapy alone might be appropriate. To know when to stoop with the medications is also a challenge for the assistant physician. Usually, when there is no more progression of the lesion for six months, the medication may be tapered off and the active disease markers (acute phase reactants, imaging findings) must be monitored. Plastic surgery or filling techniques for facial scleroderma are usually considered, especially in adolescents who are aware of their appearance. Usually, if the disease seems to be stabilized for six to twelve months and medical and physiotherapeutic techniques were not successful, surgery must be considered, with special attention to the region's blood supply.^50,55

In conclusion, morphea in children occurs more frequently in plaques, however, causes low morbidity. On the other hand, the linear forms are potentially riskier for causing physical disability – as in the segmental presentation in the limbs or, still, severe neurological involvement – as in the en coup de sabre form. These disabilities are of high impact on the patient's life, including major psychological damage.

Follow-up of the patients affected requires quick detection of new lesions or signs of inflammatory activity in old lesions. The aim of the treatment must be improvement of lesions, prevention of disabilities, rehabilitation and cosmetic improvement.

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Publication Dates

• Publication in this collection
  03 June 2009
• Date of issue
  Apr 2009