Morphea is a fibrosing inflammatory skin disorder. When it occurs in children and adolescents, the condition is also known as juvenile localized scleroderma to distinguish it from the systemic form of the disease (called juvenile systemic sclerosis or juvenile systemic scleroderma). When the term morphea is used there is no way, equivalent to juvenile localized scleroderma, of specifically denoting the disease in childhood or adolescence. In this review, we will use the term morphea in childhood to refer to the condition in the pediatric population.

There are very few studies on the incidence and prevalence of morphea. In a study of the incidence of childhood scleroderma in the United Kingdom and Ireland between 2005 and 2007, researchers found an annual incidence rate of 3.4 cases per million children for morphea of all types and 2.5 per million for linear morphea (LM).1 The authors of a US study on the epidemiology of morphea in Olmstead County (Minnesota) between 1960 and 1993, found an annual age- and sex-adjusted incidence rate per 100,000 population of 2.7 cases for morphea and 0.5 for linear morphea.2 Patients who were under 18 at diagnosis accounted for 34% of the patients with morphea and 69% of those with LM.

Childhood-onset morphea affects girls more than boys, with a female-to-male ratio of 2-3:1.3,4 Age of onset has been established at between 5 and 7 years.5,6 Mean age at diagnosis ranges from 7 to 13 years.3,4,6 In a series of 750 children with morphea, the mean interval between onset and diagnosis was 1.6 years (median 11 y, range 0-16.7 y).3 In a series of 52 patients with LM, this interval was 1.8 years (range, 15 d to 8 y).6 Other studies have identified a delay of 9 to 11 years.4,5,7

A family history of rheumatic and autoimmune diseases is reported in between 12.1%3 and 24.3%8 of cases. This proportion falls to between 6%3 and 8.8%8 in first-degree relatives. The diseases most frequently associated with morphea are rheumatoid arthritis, scleroderma, systemic lupus erythematosus and thyroiditis.3,8 The skin diseases most often associated with morphea are psoriasis (16.3%),vitiligo (2.3%), and lichen sclerosus et atrophicus (0.8%).3

Environmental factors, that is events occurring close to disease onset, have been reported in between 13.2%8 and 13.3%3 of patients. The most common were mechanical events (8.9%), including traumas and insect bites.3

The etiology and pathogenesis of morphea are poorly understood. The condition appears to be caused by interactions between inflammatory, fibrotic, and vascular processes. One hypothesis that would explain how fibrosis is triggered in morphea is the transformation of CD34+ fibrocytes into CD34- myofibroblasts and an increase in XIIIa1+ dermal dendrocytes.9 Some authors have reported the almost complete disappearance of CD34+ dermal dendritic cells and an increase in factor XIIIa1+ dermal dendrocytes in fibrosed lesions in patients with active morphea.10

Traditionally, morphea has been classified into 5 subtypes: plaque or circumscribed, linear, generalized, bullous, and deep (including subcutaneous morphea).11 The Pediatric Rheumatology European Society (PReS) has proposed a more exclusive and precise classification (Table 1).12,13 They propose replacing the term plaque morphea (PLM) with the term circumscribed morphea. This form can be further divided into superficial and deep subtypes (Table 1). In the present review, we have used the term plaque morphea because it is the one used in the studies we cite, most of which were carried out before the PReS classification was proposed.

The classification proposed by PReS also includes the term mixed morphea (MM), a variant that appears to be more common than previously believed. This decision indicates a shift towards viewing morphea as a term encompassing a spectrum of clinical variants characterized by inflammation and fibrosis occurring at different depths (Figures 1 and 2). Another factor supporting this view is the overlap between morphea en coup de sabre (ECDS) and Parry-Romberg syndrome (PRS) or progressive hemifacial atrophy, a condition that occurs in between 24% and 48% of patients.4,14,15 The PReS classification does not, however, recognize certain other subtypes, such as the bullous, deep, and subcutaneous forms of morphea.11 Traditionally, deep morphea (DM) is characterized by thickening of the skin, subcutaneous tissue, and fascia. It is a rare form, appearing in around 4% of patients with morphea.8 Subcutaneous morphea is defined by incipient involvement of subcutaneous tissue. Bullous morphea is characterized by the appearance of edema and tense dermal or subepidermal bullae secondary to lymphatic obstruction caused by fibrosis, which can also lead to edema in the limbs.16 The PReS classification proposes the inclusion of these forms as new morphea subtypes (depending on the clinical presentation)12 and the exclusion of eosinophilic fasciitis,11 lichen sclerosus et atrophicus, and atrophoderma of Pasini and Pierini as forms of morphea at the extreme end of the spectrum.17

Figure 1.

Five-year-old boy with mixed morphea (circumscribed-linear ECDS) as defined by the PReS classification. The circumscribed component is clearly visible in the plaques situated on a) the right side of the neck, and b) the right preauricular and parotic regions, including involvement of the pinna.

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Figure 2.

Five-year-old boy with mixed morphea (circumscribed-linear ECDS) as defined by the PReS classification. The linear component can be seen in the lesion on the left side of the forehead.

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Extracutaneous manifestations are observed in up to 40% of patients with morphea (Table 2).8

No correlation has been observed between abnormal laboratory test results and the activity, course, or prognosis of the disease in patients with morphea.3,8 Elevation of acute phase reactants is more common in the deeper forms of morphea, in LM, and during the inflammatory phase of the disease. An elevated white blood cell count is found in 37.5% of patients and an increased erythrocyte sedimentation rate in 25%.3 Peripheral blood eosinophilia is seen in up to 62.6% of patients with DM, falling to between 12% and 18.5% in patients with other clinical forms of the disease.3,8 Creatinine phosphokinase can be elevated in the deeper forms and this anomaly is associated with muscle pain and weakness.3 Some patients present abnormalities in immune electrophoresis of serum proteins associated with elevation of diverse immunoglobulins.3 Antinuclear antibodies have been found in up to 42.3%3 of patients; they are observed more frequently in LM, generalized morphea (GM), and the deeper forms of the disease.3,8 Rheumatoid factor is detected in 16% of children with morphea.3

There are numerous options for the treatment of morphea, including phototherapy, topical corticosteroids, topical calcipotriol, oral calcitriol, topical tacrolimus, systemic corticosteroids, methotrexate, mycophenolate mofetil, intralesional gamma interferon, ciclosporin A, D-penicillamine, imiquimod, bosentan, infliximab, etanercept, adalimumab, hydroxychloroquine, and photopheresis.18,19 In many cases there is insufficient evidence to support the use of these treatments in this setting, even in the case of drugs as widely used as topical corticosteroids.19 The variation observed in the treatments used is remarkable and tends to be related to the specialty (dermatology or rheumatology) of the prescribing physician.19 To date, there has been only 1 systematic review of studies on the treatment of patients (children and adults) with morphea.20 In this review we only mention drugs that have been studied in children and adolescents (Table 3).

The findings of numerous studies support the use of phototherapy in morphea; most of the evidence comes from uncontrolled, open-label studies and case series. While few children were enrolled in the studies, the efficacy of low-dose UV-A1, medium-dose UV-A1, narrowband UV-B, and topical psoralen-UV-A (PUVA) have all been assessed in this age group. We found only one study that enrolled only children.21

The only randomized controlled trial (RCT) in patients with morphea compared the efficacy of low-dose UV-A1, medium-dose UV-A1, and narrowband UV-B phototherapy.22 The authors of that study did not blind the assessment of the primary outcome (the Modified Skin Score). The study enrolled 66 patients with PLM, LM, ECDS, DM, and GM aged between 5 and 73 years. All three phototherapy regimens achieved statistically significant reductions in the Modified Skin Score and improved histological and ultrasound findings. Medium-dose UV-A1 was more effective than narrowband UV-B, but no differences were found between low- and medium-dose UV-A1, or between low-dose UV-A1 and narrowband UV-B.

An open-label prospective study assessed the efficacy of low-dose UV-A1 (20J/cm2) in 19 pediatric patients with PLM, LM, PRS, and DM.21 In addition, all the patients applied calcipotriol ointment (0.005%) twice daily. A statistically significant reduction of 67.1% was observed in the Modified Skin Score following treatment. Two children reported mild skin irritation, which was attributed to calcipotriol.

The authors of a controlled intrapatient study that compared the efficacy of medium-dose and low-dose UV-A1 in patients with PLM found significant differences between the 2 regimens in the ultrasound assessment.23

PUVA-bath (8-methoxy-psoralen) photochemotherapy was used in an uncontrolled open-label prospective study.24 The study included 17 patients between 9 and 72 years of age with PLM, LM, and GM. The authors reported improvement in 13 of the patients both on a clinical scale and in terms of ultrasound and histologic indications.

Finally, isolated cases of pansclerotic morphea in childhood treated with oral PUVA25,26 and UV-A phototherapy have been reported.27

Topical calcipotriol was used in association with low-dose UV-A1 in the study mentioned above.21

The efficacy of oral calcitriol (1,25-dihydroxycholecalciferol) was assessed in an uncontrolled open-label prospective study of 7 pediatric patients with LM; the lesions improved in 5 of the 7 children according to a clinical scoring system.28 No adverse effects were reported. In a double-blind RCT, oral calcitriol did not demonstrate greater efficacy than placebo in 27 adults.29

Tacrolimus 0.1% has been used with good results in several small studies with adults.30,31 However, a case of bullous morphea in childhood that did not respond to treatment with tacrolimus 0.1% has also been published.16

In an open-label study, 9 children with PLM were treated with imiquimod 5% cream for 9 months.32 Imiquimod reduced both the mean score on the visual analog scale (VAS) and skin thickness on high-resolution ultrasound. However, the reduction observed on the DIET score (depigmentation, induration, erythema and telangiectasia) was not statistically significant. One patient experienced ulceration that required temporary discontinuation of treatment.32

Methotrexate (MTX) is often used to treat the different forms of morphea in childhood. The usual regimen is a dose of 10 to 15mg/m2/w, administered orally or subcutaneously33–35 (0.3-0.6mg/kg).36 This regimen is often complemented by folic acid and, during the early weeks of treatment, an induction phase of systemic corticosteroid therapy, generally in the form of intravenous boluses of methylprednisolone at a dose of 30mg/kg/d (pulsed intravenous corticosteroid combined with methotrexate therapy [PCMT]).6,33,35,36 Oral prednisone may be added to this regimen.33 The combination of MTX and corticosteroid therapy appears to be more effective than the use of either drug alone.6 Treatment duration varies, and patients may continue on this regimen for several years.6,34,37 Data on 34 cases of children with morphea treated with PCMT for between 1 and 3 years was analyzed in a retrospective study.33 The regimen stopped disease progression in 94% of the patients and 24 patients (71%) had no signs of active disease at the end of the follow-up period (0.2-7 years). In 16 (47%) patients, therapy was discontinued when the disease was considered to be inactive (a mean of 20 ± 12 months). Of these, 7 (44%) experienced a relapse following withdrawal of treatment.

A double-blind RCT published in 2011 compared the efficacy of oral MTX 15 mg/m2 and placebo.34 Pediatric patients were randomized to receive MTX or placebo once weekly, for 12 months or until treatment failure. Both groups also received oral prednisone 1 mg/kg/d for the first 3 months. A target lesion was selected for clinical assessment with thermography and a computerized scoring system based on a skin score rate (SSR) evaluation. Response to treatment was defined by 3 criteria: 1) a decrease in temperature of at least 10% over baseline; 2) SSR of at least 1; and 3) the absence of new lesions. Relapse was defined as a failure to meet any 1 of these criteria. The study enrolled 70 patients aged between 6 and 17 years with various morphea subtypes (44 with LM, 18 with GM, and 8 with MM). Statistically significant differences between the 2 groups were found in thermography and SSR, but not in the appearance of new lesions. Relapse occurred in 46% of the patients who completed the 12-month treatment period (32.6% in the MTX group and 70.8% in the placebo group; P < .005). The side effects reported were mild and in no case led to discontinuation of treatment. In an open-label extension of that study using the same response criteria, 65 patients were treated with MTX 15 mg/m2 for 12 months, followed by a tapered regimen of MTX.37 On follow-up, 35 of the 65 patients maintained clinical remission for a mean of 25.6 months (median 24, range 6-48). Of the 65 patients, 10 did not respond to treatment, 8 relapsed before completing 12 months of MTX, 5 relapsed when the regimen was tapered, and 7 were lost to follow-up.

Although prognosis in patients with morphea has been little studied and long-term studies are particularly scarce, the available evidence suggests that the disease tends to run a chronic or intermittent-recurrent course and frequently causes sequelae. In the short and medium term, systemic treatment with MTX and/or corticosteroid therapy appears to stop the progression of the disease and/or improve lesions.6,33,34,37 However, the condition recurs in between 28% and 46% of patients within 20 months of cessation of treatment.33,34,70 Activity persists in between 28% and 89% of patients in the long term.6,71 In a survey of patients with LM conducted after follow-up of up to 20 years, all but one of the respondents reported having residual damage.6 This included cosmetic sequelae in 66% and functional limitations in 38%. In total, 51% of those surveyed considered that the treatment they had received had been effective. Finally, individuals who develop morphea in early childhood may have decreased quality of life and be more likely to develop autoimmune conditions in later life.71

The term morphea encompasses a broad spectrum of clinical forms which have considerable potential for causing long-term sequelae, making early diagnosis and appropriate treatment very important.

Although little used in routine clinical practice, instruments for determining morphea activity are a useful aid when making therapeutic decisions. The existing clinical scales appear to reflect the state of the disease objectively and correlate one with another; however, their use requires more time than is usually available in routine clinical practice. High-resolution ultrasound has high sensitivity and high specificity for morphea, but nonetheless requires time, specific equipment, and appropriate training.

The treatments for children supported by the highest quality of evidence (based on epidemiological studies) are phototherapy and the PCMT regimen. The form of phototherapy used in most of the studies in the literature was low-dose UV-A1, an option not readily available in Spain. However, 1 study found no differences between low-dose UV-A1 and narrowband UV-B. However, long-term outcomes in patients treated with phototherapy have not been documented.

In summary, PCMT has been shown to be effective in the control of morphea in the short and medium term. However, since morphea is a chronic disease characterized by intermittent outbreaks and periods of remission, new treatment strategies and long-term follow-up studies are needed.

The authors declare that they have no conflicts of interest.