Localized Scleroderma

28

  CHAPTER

Localized Scleroderma Suzanne C. Li, Elena Pope

Scleroderma refers to hard skin that develops because of an excessive accumulation of collagen.1 In the localized form (localized scleroderma [LS], also called morphea), inflammation in the skin and subcutaneous tissues triggers the fibrosis. LS and the systemic form, systemic sclerosis (SSc), are chronic diseases that share some pathophysiological pathways but differ greatly in their clinical features and morbidities. LS is usually unilateral, less extensive, and has a different pattern of extracutaneous involvement. The prognosis is generally much better for LS than SSc but depends upon subtype, response to treatment, and extracutaneous involvement.

HISTORICAL REVIEW Addison is credited with describing areas of skin hardness that he called keloids in 1854.2 In 1868, Fagge pointed out similarities between Addison’s keloids and scleroderma, and described different forms of localized scleroderma, including sclerodermie en coup de sabre, and the atrophy associated with linear forms.3 Parry–Romberg syndrome was described by Parry in 1825 and Romberg in 1846.4 Eulenburg provided the name progressive facial hemiatrophy for this subtype in 1871.4 The first reported case of disabling pansclerotic morphea may have been that of Roudinesco and Vallery-Radot in 1923.5

DEFINITION AND CLASSIFICATION LS is an umbrella term encompassing a large spectrum of clinical presentations and severities. The Mayo classification divides LS into five general types: (1) plaque morphea, (2) generalized morphea, (3) bullous morphea, (4) linear morphea, and (5) deep morphea.6 Because this classification includes some conditions that are not uniformly accepted as LS subtypes (atrophoderma of Pasini and Pierini, eosinophilic fasciitis, bullous morphea, and lichen sclerosus et atrophicus) and omits a category (mixed morphea), which accounts for 15% to 23% of juvenile LS cases,7-9 a revision of the classification was developed by the Pediatric Rheumatology European Society (PRes).10 It includes five subtypes: (1) circumscribed morphea, (2) linear scleroderma, (3) generalized morphea, (4) pansclerotic morphea, and (5) the new mixed subtype in which a combination of subtypes is present (Table 28-1). Three forms of the plaque morphea subtype of the Mayo classification (morphea en plaque, guttate morphea, and keloid morphea) are included in the superficial type of circumscribed morphea, and two forms of deep morphea (subcutaneous morphea and morphea profunda) are included in the deep type of

406

circumscribed morphea of the PRes classification.6 One of the other deep morphea forms, disabling pansclerotic morphea of children, is put into its own separate category in the PRes classification. Generalized morphea and linear morphea are similar between the two classifications, with the PRes classification dividing the linear scleroderma subtype into two types based on lesion location (trunk/limbs or head). Bullous morphea is not included in the PRes classification, as bullous lesions may represent a reaction related to lymphatic dilatation or trauma rather than indicating a specific subtype.11 Circumscribed morphea refers to oval or round lesions that are centrally indurated with a waxy, ivory color and a violaceous rim (Fig. 28-1). There are two depths of involvement. Superficial circumscribed morphea is confined to the epidermis and superficial dermis, initially presenting with skin discoloration and minimal skin thickening and resolving with hyperpigmentation and mild skin depression with visible venous pattern. Deep circumscribed morphea affects the deeper dermis and subcutaneous tissues, resulting in tight and bound down skin. Circumscribed morphea lesions occur most frequently on the trunk and less often on the extremities. The face is usually spared. Guttate morphea is a rare variant of superficial circumscribed morphea that presents as multiple small (2 to 10 mm), initially erythematous or violaceous, and later yellowish or whitish sclerotic lesions with a shiny or depressed surface.6,12 These lesions can develop hypopigmentation or hyperpigmentation, and primarily affect the trunk.6 Generalized morphea (Fig. 28-1B) consists of four or more individual lesions, typically with a diameter larger than 3 cm, involving at least two out of seven anatomical sites (head-neck, right upper extremity, left upper extremity, right lower extremity, left lower extremity, anterior trunk, posterior trunk). Unilateral generalized morphea usually begins in childhood.13 Linear scleroderma is the most common subtype of LS in children and adolescents, and is characterized by one or more longitudinal, bandlike lesions that typically involve upper or lower extremities.8,14,15 The lesions may not appear contiguous at the outset, but they have a linear configuration and may coalesce later. The distribution of the lesions frequently follows Blaschko’s lines, an embryonic pattern that may represent genetic mosaicism.8,16,17 Linear lesions may start superficially and remain so, or become progressively more indurated, bound down with various degrees of involvement of dermis, subcutaneous tissue, and underlying muscle to bone (Fig. 28-2). Linear lesions of the face or scalp are called the en coup de sabre (ECDS) variety, due to the resemblance to a sword stroke (Fig. 28-3). Extension onto the scalp causes scarring alopecia, which is often irreversible. Progressive hemifacial atrophy, which is also known as Parry– Romberg syndrome (PRS), is a form of linear scleroderma of the head

TABLE 28-1  Classification of Juvenile Localized Scleroderma MAIN GROUP

SUBTYPE

DESCRIPTION

(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 fascia, and may involve 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 dermis, subcutaneous tissue, and sometimes muscle and underlying bone, and affecting the limbs and/or the trunk. En coup de sabre (ECDS). Linear induration that affects the face and/or the scalp and sometimes involves muscle and underlying bone. Parry–Romberg syndrome (PRS) or progressive hemifacial atrophy (PHA). Loss of tissue on one side of the face that may involve the dermis, subcutaneous tissue, muscle, and bone. The skin is mobile. Induration of the skin starting as individual plaques (four or more and larger than 3 cm) that become confluent and involve at least two out of seven anatomical sites (head-neck, right upper extremity, left upper extremity, right lower extremity, left lower extremity, anterior trunk, posterior trunk) 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 organs 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 [linear-circumscribed])

(b) Deep

(2) Linear scleroderma

(a) Trunk/limbs (b) Head

(3) Generalized morphea (4) Pansclerotic morphea (5) Mixed morphea

Associated conditions: eosinophilic fasciitis, bullous morphea, lichen sclerosus et atrophicus, and atrophoderma of Pasini and Pierini can be concomitant, or precede or follow each of the localized scleroderma subtypes, but are not included in the classification. From Laxer and Zulian (Ref. 10).

A

B

C

D FIGURE 28-1  Circumscribed morphea. A, Marked erythema, early central area of thickening with a waxy appearance. B, Multiple coexistent plaques displaying activity features: yellow-white discoloration, skin thickening surrounded by a violaceous border, and outer erythema. C, Active lesion with central, waxy infiltration surrounded by violaceous border; mild epidermal and superficial dermal atrophy is also noted with visible venous pattern. D, Active plaque with marked central thickening/sclerosis surrounded by a thin “lilac” ring.

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SECTION THREE  Systemic Connective Tissue Diseases

FIGURE 28-2  Linear morphea. A, Yellow-white sclerotic plaques coalescent into a linear configuration, crossing over the knee joint. B, Linear distribution of a band of subcutaneous atrophy involving the forearm, hand, and third, fourth, and fifth fingers with associated contractures of affected fingers.

A

B

FIGURE 28-3  En coup de sabre variant of morphea. A, Linear band across the forehead, with a waxy infiltration toward the eyelid causing dermal and subcutaneous atrophy, and eyebrow and eyelash losses. B, Linear band across the forehead with extension onto the scalp with hyperpigmentation, dermal and subcutaneous atrophy, and scarring alopecia.

that may occur with or without ECDS18,19 (Fig. 28-4). The hallmark of this presentation is varying degrees of atrophy below the forehead, affecting the subcutaneous fat, muscle, and underlying bone structures, with mild or absent epidermal and dermal changes.10,20 Extensive cases usually cause marked hemifacial atrophy, resulting in severe facial asymmetry and major permanent disfigurement. Disabling pansclerotic morphea of childhood is extremely rare and the most severe subtype of LS because it is widespread, has fullthickness skin involvement, and commonly involves underlying muscle and bone. There is circumferential involvement of all affected anatomic sites, except for the fingertips and toes, which are usually spared.5 Skin tightness may lead to chronic extensive ulcers with a potential for development of squamous cell carcinoma.21

The mixed subtype results from a combination of two or more subtypes, such as linear scleroderma and circumscribed morphea, or linear scleroderma and generalized morphea, and can be seen in up to 23% of the cases.9

Associated Conditions Several skin disorders can precede, coexist, or follow LS.10 Lichen sclerosus et atrophicus presents as violaceous discoloration progressing to shiny, white, superficial plaques. Typical locations are in the anogenital area and over the wrists and ankles. Sometimes clinical distinction from circumscribed morphea may be difficult. Genital involvement creates an “hourglass” appearance due to the discoloration surrounding the vaginal and perianal area. It is usually

CHAPTER 28  Localized Scleroderma

A

409

B

FIGURE 28-4  Parry–Romberg syndrome. A, En coup de sabre linear scleroderma of approximately 2 years’ duration affects the chin just to the left of midline resulting in a depression and mild asymmetry of the jaw. B, En coup de sabre linear scleroderma involves the left face with hyperpigmentation, atrophy of subcutaneous tissues, and early hemifacial atrophy. (Pictures courtesy R. Laxer and F. Zulian).

accompanied by significant pruritus and/or burning sensation due to fissuring. Occasionally hemorrhagic blistering may develop, raising concern about child abuse. There is a high prevalence of lichen sclerosus et atrophicus in patients with circumscribed and generalized morphea.22 Atrophoderma of Pasini and Pierini is characterized by asymptomatic hyperpigmented, atrophic patches, with well-demarcated, “cliffdrop” borders (Fig. 28-5, B). These lesions, primarily seen on the trunk, lack the typical inflammatory changes of circumscribed morphea and may represent the “burned-out” phase of deep morphea. Bullous morphea is extremely rare, occurring with most subtypes, including typical circumscribed morphea. The pathogenesis of the bullous lesions is not well understood; local lymphatic obstruction from collagen deposition may play a role.11,23 Eosinophilic fasciitis is a rare presentation of primarily fascial involvement with hypergammaglobulinemia, eosinophilia, and high inflammatory markers.24-27 Eosinophilic fasciitis starts as painful swelling with progressive induration and thickening of the skin creating a typical “peau d’orange” appearance. It tends to involve extremities, and in pediatric patients, often the hands and feet.28

EPIDEMIOLOGY LS is rare, with an estimated incidence of 0.34 to 2.7 cases per 100,000 per year.16,29 It appears to be more prevalent in the white population (73% to 82%).8,9,14,29 Pediatric prevalence is estimated at 50 per 100,000. In a current U.S. registry of over 8000 pediatric rheumatology patients (Childhood Arthritis Rheumatology Research Alliance [CARRA] registry), LS is 17 times less common than juvenile idiopathic arthritis and 3 times less common than systemic lupus erythematosus. Most pediatric patients develop the disease in the first decade of life.30

The mean age of onset ranges from 6.4 to 10.5 years, and median age from 6.1 to 8.1 years.8,9,14,17,29,31-33 The female-to-male ratio in children is 1.7-3.7:1, lower than that reported for adults (2.6-7:1).9,16,31,34 No significant difference in age of onset or sex ratio has been found between subtypes for children.8,14 Most pediatric patients have the linear scleroderma subtype (51% to 74%), either alone or as part of the mixed morphea subtype, followed by circumscribed morphea and mixed morphea.8,9,14,29,32,33 Recent studies report subtype frequencies of 41.8% to 66.7% for linear scleroderma, 15% to 36.8% for circumscribed morphea, 3% to 23% for mixed morphea, and 6.6% to 11% for generalized morphea.8,9,14,29,32,33 Pansclerotic morphea is extremely rare, with only 5 pansclerotic morphea patients reported in more than 1100 juvenile LS patients.8,16,31,33 Adults have a different subtype distribution, with circumscribed morphea the most common presentation (43.9% to 69%), followed by generalized morphea (8% to 23.6%), linear scleroderma (9.8% to 10%), and mixed morphea (3.5% to 11%),9,16,31 although one study reported a distribution of 13.2% circumscribed morphea, 52.6% generalized morphea, and 21.7% linear scleroderma.34 Pansclerotic morphea is also extremely rare in adults.35 The variable presentations combined with disease rarity result in frequent delays in diagnosis; pediatric studies report a mean time between initial symptom and diagnosis of 11 to 21.6 months,8,14,36,37 and in over 30% of LS patients in the CARRA registry, a diagnosis was not made for 5 or more years.38

ETIOLOGY AND PATHOGENESIS The etiology and pathogenesis of LS are not completely understood, but they seem to share many similarities with SSc.39 A recent gene

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SECTION THREE  Systemic Connective Tissue Diseases

A

B

C

FIGURE 28-5  Late-stage morphea lesions. A, Visible venous pattern due to epidermal and dermal atrophy. B, Hyperpigmentation and dermal loss with a “cliff-drop” appearance. C, Marked areas of dermal and subcutaneous atrophy.

expression profiling study of scleroderma patients found a common inflammatory pattern for LS and diffuse and limited SSc patients, and additional unique patterns for diffuse and limited SSc.40 A complex interplay of genetic predisposition, autoimmunity, and environmental factors leads to local inflammation and ultimately increased collagen synthesis and deposition in the skin.41,42 The proposed initiating event is endothelial cell injury resulting in release of cell mediators, upregulation of cell adhesion molecules such as intracellular (ICAM), vascular (VCAM), endothelial leukocyte (E-selectin), and the recruitment of neutrophils. Th-1 and Th-17 immune responses are characteristic for early stages of the disease.42 The release of interferon (IFN)-γ, interleukin (IL)-2, -6, and -8, and tumor necrosis factor (TNF)-β are thought to be responsible for the increased inflammatory responses. Patients with LS have evidence of upregulation of IL-6 and IL-2R compared with controls.43,44 On the other hand, high levels of Th-2 cytokines (IL-4, -6, -8, and -13) tend to correlate more with disease damage and fibrosis.42 Patients with LS have elevated serum levels of B-cell activating factors belonging to the transforming growth factor (TGF) family.45 Upregulation of TGF-α and TGF-β induces production of platelet-derived growth factor (PDGF); connective tissue growth factor (CTGF); and IL-2, -4, -6, -8, and-13, and soluble receptors (IL-2R and IL-6R), which results in increased mitogenic activity of fibroblasts and production of collagen.42,46 In one study, the elevated serum levels of TGF correlated with the severity of LS and the presence of antihistone anti­bodies.45 Milder cases of LS, such as circumscribed morphea, have levels of TGF-β1 similar to those of healthy controls.47 The increased production of collagen is further augmented

by the decrease in the enzymatic degradation of collagen due to inhibition of matrix metalloproteinases (MMPs).48 An autoimmune pathogenesis for LS is supported by the frequent occurrence of autoantibodies, concurrent autoimmune conditions, and family history of autoimmune conditions. A positive antinuclear antibody (ANA) has been found in 26% to 59.4% of juvenile LS patients, with homogeneous, speckled, and nucleolar the most commonly identified patterns.9,14,31,33,49,50 It is estimated that 5% to 10% of patients with LS have other autoimmune diseases.9,14,51,52 The frequency of a concurrent autoimmune disease is higher in adults (30%).9 A 17% to 26% frequency of a concurrent autoimmune disease was reported in juvenile LS patients at median disease durations of 12 to 13 years,53,54 suggesting that autoimmunity may increase in LS patients over time. However, a cross-sectional study did not find any relationship between age of onset or disease duration and concurrent autoimmunity.55 A family history of autoimmune conditions is present in 11% to 24% of cases.8,9,14,51 The presence of chimeric infiltrating cells in the biopsies of affected skin and similarities to the clinical and histopathological findings of chronic graft-versus-host disease suggest that chimerism may be involved in the pathogenesis of the disease.56 An environmental factor, including medication, infection, or trauma may be the initiating event in some cases of LS.8,49,57 Some medications (bisoprolol, bleomycin, bromocriptine, carbidopa, d-penicillamine, and ergot) have produced scleroderma-like lesions.58,59 Recent studies report the association of anti–TNF-α medications with onset of LS although these agents have also been used to treat LS.60,61

CHAPTER 28  Localized Scleroderma A toxin contained in some lots of L-tryptophan was implicated in a large epidemic of eosinophilia-myalgia syndrome, a disease similar to eosinophilic fasciitis and LS.62,63 Among infectious agents, Borrelia species organisms have been extensively studied; at present this etiological link is not supported by the existing evidence, especially outside Europe.7,48,64 Typical LS lesions have been reported after local contusion; injection with aluminum-absorbed allergen extracts for allergy desensitization, mepivacaine, pentazocine, vaccinations, vitamin B12, or vitamin K1; and radiation treatment.58,65-69 A preceding history of trauma at the lesion site was reported in 23% to 35.7% of linear scleroderma patients,49,70 and 11.8% of circumscribed morphea patients.70 More recent larger juvenile LS studies have reported frequencies of 9% to 12% of a local mechanical event (trauma, insect bite, or vaccination) prior to disease onset8,14; there may be a higher frequency of preceding trauma in patients with Parry–Romberg Syndrome.71-73 Trauma and vigorous exercise may also be inciting events for some cases of eosinophilic fasciitis.24,74

411

A

Clinical Manifestations The presentation of LS varies, related to differences in subtype, site of involvement, extracutaneous involvement, and disease duration. Because diagnosis is often delayed, patients commonly show signs of both activity and damage. Most patients have subtle, slowly evolving skin lesions, but some—especially those with pansclerotic morphea— develop rapidly progressive skin and deep tissue involvement. In a few patients, skin lesions only develop after they are diagnosed with arthritis or a neurological problem.8,75-77 Rarely, LS is evident at birth as areas of faint violaceous discoloration or atrophy without epidermal changes.78 The skin discoloration can be easily mistaken for a nevus flammeus or port-wine stain,79 whereas areas of atrophy may raise the possibility of either localized lipoatrophy or early stages of generalized lipodystrophy syndromes. Early skin lesions, reflecting the initial inflammatory phase, are often erythematous to violaceous plaques with normal skin texture and thickness.6,7,80 Erythema varies from subtle pink to deep red, with some lesions showing a combined erythematous-violaceous color (Fig. 28-1). Over time, fibrosis becomes more prominent; lesions can develop induration with a central white to yellow, waxy area surrounded by an erythematous or violaceous margin (lilac ring)6,7 (Fig. 28-1). Later on, damage features predominate. These include postinflammatory hyperpigmentation; atrophy of epidermis (shiny skin with visible venous pattern), dermis (loss of hair follicles and adnexal structures, and cliff-drop atrophy) and subcutaneous tissue (loss of fat) (Fig. 28-5); and progressive skin thickening7 (Fig. 28-6). More than 20% of juvenile LS patients have extracutaneous manifestations, including musculoskeletal, neurological, vascular, ocular, and gastrointestinal involvement.14,52 Extracutaneous manifestations can occur in any subtype, with risk for their development not associated with age of disease onset or disease duration.9,14,51,52 Subtype and lesion location influence the type of extracutaneous manifestation: growth defects (undergrowth) of extremities, trunk, and face/head are associated with linear scleroderma10,31; and neurological, oral, and ocular problems are associated with linear scleroderma of the head.9,51,52 Joint involvement is associated with linear lesions of extremities, and with pansclerotic, generalized, and deep morphea.5,9,14,51 Extracutaneous manifestations are usually related to the anatomic site of the skin lesion, but involvement remote from the lesions has been reported in 25% or more of those with arthritis, neurological, or ocular problems.52 Between 4% and 9% of patients have multiple extracutaneous manifestations, with the risk higher in patients with neurological or ocular involvement.14,52,75,81

B FIGURE 28-6  Inactive morphea. A, Band of bound down, sclerotic skin. B. Linear morphea causing hyperpigmentation, sclerotic bands, atrophy, and contractures.

Musculoskeletal problems include arthralgia, arthritis, limited range of motion, contractures, and scoliosis.31 Oligoarticular or polyarticular arthritis has been reported in 12% of childhood-onset LS patients.52 Muscle atrophy, myositis, muscle spasm, osteomyelitis, and bone and soft tissue growth defects also occur. Musculoskeletal problems are the norm for patients with pansclerotic morphea who are also at risk for soft-tissue calcifications and secondary osteoporosis.5,82 Growth defects may be subtle until the child has a growth spurt that makes the asymmetry obvious. Defects can be severely disabling or disfiguring; limb length differences of 7 cm have been reported,83 and patients with PRS can have severe facial hemiatrophy (Fig. 28-4).71 Lesions on the head are often associated with neurological, ocular, oral, and bone problems. Neurological problems have been found in 4.4% to 10% of children with LS, with seizures and headache most commonly reported.14,52,75,84 Seizures include absence, complex partial, generalized tonic clonic, and status epilepticus, and can be refractory to treatment.75,85 Other neurological problems include cranial nerve palsies, trigeminal and peripheral neuropathy, neuropsychiatric problems, movement disorders, slurred speech, cognitive problems, cavernomas, and central nervous system vasculitis.32,75,85,86

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SECTION THREE  Systemic Connective Tissue Diseases

Ocular involvement has been found in 2.1% to 6% of children with LS.9,36,52 The most common ocular complications are fibrotic changes in eyelids, eyelashes, or lacrimal gland and anterior segment inflammation (uveitis, episcleritis).81 Many other ocular and vision problems have been reported, including hemianopsia, diplopia, ptosis, keratitis, strabismus, acquired glaucoma, enophthalmos, orbital myositis, pupillary mydriasis, and papilledema.81,85 Because eye involvement can be asymptomatic, patients with facial or head lesions should undergo routine ophthalmological monitoring. Defects in growth of the lower third of the face, skeletal malocclusion, and paranasal sinus defects occur frequently in children with facial lesions.87 These children are at risk for delayed permanent tooth eruption, root resorption and underdevelopment, impaired mandibular movement, and masticatory contractions or spasms.87 Hemiatrophy of the tongue may occur in half of the children with PRS.71 Gastrointestinal, pulmonary, cardiac, and renal problems are uncommon in most patients with LS (1% to 2.6%) and rarely lifethreatening.14,31,52,88 The most common gastrointestinal problem is gastroesophageal reflux. More children with LS may have asymptomatic esophageal abnormalities.74 A few children with LS have dyspnea, chronic cough, or respiratory insufficiency, and they can be found to have a restrictive pattern and/or a decreased diffusion capacity for carbon monoxide on pulmonary function tests14,31,52 Conduction abnormalities including ventricular premature beats and right bundle branch block have been found in LS.89,90 A 10-year prospective study found children with LS developed asymptomatic hypertension and diastolic dysfunction at a significantly higher frequency than healthy controls.89,90 Abnormal pulmonary function tests have been found in more than 25% of patients with pansclerotic morphea, who may also be at risk for more serious cardiac involvement including decreased ejection fraction and cardiomyopathy.5,21,91 Eosinophilic fasciitis, unlike LS, usually manifests as acute onset of painful rapidly progressive symmetric involvement of the extremities. Early on, there is edema and erythema, followed by induration and dimpling of the skin giving a peau d’orange appearance, with progressive fibrosis of the subcutaneous tissues causing a bounddown, rock-hard consistency.28,92-94 Joint contractures and myositis are common in children, and 25% to 44% have polyarthritis.28,74,93 Up to 29% may have LS lesions of eosinophilic fasciitis.92

PATHOLOGY Histological documentation is helpful but not essential in confirming the clinical diagnosis. The findings are dependent on the stage of the sampled lesion. Ideally, biopsies should be taken from a relatively active border (infiltrative, red and warm lesion). Older sclerotic lesions provide less diagnostic clarity. Early inflammatory stages are characterized by a mixed perivascular and periadnexal infiltrate of predominantly lymphocytes with rare plasma cells and eosinophils in the reticular dermis. There may be dermal edema, swelling and degeneration of collagen fibers, and some thickened collagen bundles.36,95 Histiocytes may surround individual collagen fibers, creating a “floating” appearance.96 ECDS variant may present with more prominent vacuolar degeneration at the dermoepidermal junction.97 Goh et al. described a pattern of perineural lymphoplasmacytic infiltration in alopecia occurring in an ECDS lesion,98 an interesting potential mechanism explaining linearity and multiple tissues involvement. In the later stages of the disease, the inflammatory infiltrate is minimal or absent, replaced by excessive deposition of dense collagen, with a shift from type III to type I collagen.99 The eccrine glands become atrophied and the subcutaneous fat appears “trapped” in the

dermis because of the extension of collagen into the subcutaneous tissues. Blood vessels walls are thickened. The characteristic histological findings of lichen sclerosus et atrophicus are an atrophic epidermis, edema, and homogenized hyalinized collagen in the papillary dermis. These changes can also be found in LS plaques, typically associated with additional alterations as listed previously.8,16,100 Eosinophilic fasciitis is characterized by a significant inflammatory infiltrate (lymphocytes, plasma cells, and eosinophils) at the dermohypodermal junction, dense collagen, and thickening of the fascia. Inflammation and later fibrosis in the hypodermis is robust and also found in the muscle and reticular dermis, and the epidermis can show atrophic changes.101,102 The sparing of the papillary dermis, marked inflammatory infiltrate, and presence of eosinophils should allow pathological differentiation from classical LS lesions.103 The histopathological differentiation between LS and SSc is sometimes difficult, as both biopsies show increased amounts of abnormal collagen and perivascular, interstitial, and periadnexal inflammation.95 However, in LS the inflammatory infiltrate is more intense and often found at the dermal–subcutaneous junction, a site not involved in SSc inflammation.95 In addition, because collagen bundles are distributed throughout the dermis in LS but concentrated in the lower reticular dermis in SSc, the papillary dermis shows sclerosis in LS but not in SSc.95

DIFFERENTIAL DIAGNOSIS The manifestations of localized scleroderma are easily overlooked or attributed to other etiologies, particularly in the early stages (Table 28-2).36,104 Early recognition is important because it allows inter­ vention limiting the ultimate damage. Generalized or pansclerotic morphea may pose more diagnostic dilemmas; differentiation from systemic variants of scleroderma may sometimes be difficult. Children with LS, in contrast to children with SSc, rarely develop Raynaud phenomenon or internal organ involvement (lung, kidney, gastrointestinal). There is also a difference in the pattern of skin involvement: pansclerotic and generalized morphea can affect the entire back, whereas SSc generally spares the central back and more severely affects the fingers and hands.105 Deep forms of morphea that manifest with contractures of the hands, arthralgias, and sometimes synovitis require further testing to differentiate them from juvenile idiopathic arthritis or other rheumatic diseases, although LS can coexist with these diseases in some patients. As children with LS may also have a positive test for ANA, the absence of erosive joint disease and laboratory findings such as the presence of antihistone antibodies (AHAs), elevated muscle enzymes, and eosinophilia may help to differentiate LS from juvenile idiopathic arthritis.

LABORATORY EXAMINATION There are no diagnostic or characteristic laboratory findings for LS; it is diagnosed based on clinical findings. A biopsy is sometimes needed to distinguish LS from other conditions. The diagnosis of eosinophilic fasciitis requires documentation of fascia involvement, either on biopsy or magnetic resonance imaging (MRI) findings of hyperintensity and enhancement of fascia.28 Patients with eosinophilic fasciitis usually have an elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), eosinophilia, and hypergammaglobulinemia.74,106,107 Some have elevated muscle enzymes, with aldolase more commonly elevated than creatine kinase (CK).108 The same abnormalities are infrequently found in children with LS, primarily in those with deeper, more extensive disease,

CHAPTER 28  Localized Scleroderma

413

TABLE 28-2  Differential Diagnosis of Localized Scleroderma INFLAMMATORY PHASE • • • •

Port-wine stain Lichen sclerosus et atrophicus Bruising Annular erythemas (erythema migrans, tinea corporis, erythema marginatum, acrodermatitis chronica atrophicans) • Eosinophilic fasciitis

INFILTRATIVE (INDURATED) PHASE • • • • • • •

• • • •

Systemic sclerosis Lipodermatosclerosis Pretibial myxedema Panniculitis Eosinophilic fasciitis Chronic graft-versus-host disease Connective tissue/smooth muscle hamartomas (collagenoma, elastoma, smooth muscle, and fibrous hamartoma) Nephrogenic skin sclerosis Eosinophilia, myalgia syndrome Progeria Scleredema

such as pansclerotic morphea, and in some children with active linear scleroderma or generalized morphea.5,8,14,21,106 For both eosinophilic fasciitis and LS, abnormal tests tend to normalize as the disease becomes less active.49,108 In pediatric eosinophilic fasciitis, unlike adult disease, hematological abnormalities are uncommon.74,93 Many autoantibodies are found in LS. ANA positivity ranged from 42.3% to 50% in three large juvenile LS cohorts.8,38 ANA was associated with extracutaneous manifestations in one study, and with more extensive skin involvement in linear scleroderma in another.50,52 Rheumatoid factor (RF) is found in 15.9% to 26% of LS patients, more frequently in those with arthritis or other extracutaneous manifestations.8,52,109 In linear scleroderma, antihistone antibodies and anti-single-stranded DNA antibodies (ssDNA ab) have been associated with activity, extensive disease, and joint contractures or functional limitation.49,50,110 Single-stranded DNA antibodies have also been associated with muscle disease.111 Antiphospholipid antibodies (anticardiolipin, lupus anticoagulant, anti-phosphatidylserine–prothrombin complex) have been found most commonly in generalized morphea.8,112,113 Only rarely have patients had thromboembolic events, most commonly with antiphosphatidylserine–prothrombin complex antibodies.112 Other antibodies such as antitopoisomerase I antibody and anticentromere antibody, two antibodies commonly associated with SSc, are rare in LS (3.2% and 1.7%, respectively).8 Neither antibody is associated with presence of extracutaneous manifestations. About 30% of children with eosinophilic fasciitis were found to have ANAs, and 10% had RF.74,93 An initial screen of a child with new-onset linear, deep, or more extensive LS could include a complete blood count, ESR, CRP, transaminases, CK, aldolase, ANA, AHA, and ssDNA antibody. Elevations in transaminases, CK, and/or aldolase suggest possible muscle involvement, and these abnormalities, as well as an elevated eosinophil count, ESR, or CRP can be tracked during treatment. If a positive ANA, RF, anti-ss DNA, and/or antihistone antibody is found, more careful monitoring may be advisable as these markers can be associated with more severe or extensive disease.

Disease Monitoring Several semiquantitative clinical scoring measures have been used to evaluate patient response during treatment. Current measures score

INACTIVE (“DAMAGE”) PHASE PRIMARILY SKIN

PRIMARILY JOINTS

• • • • •

• • • • • •

Postinflammatory hyperpigmentation Vitiligo Lipoatrophy (localized/generalized) Porphyria cutanea tarda Bleomycin-induced flagellate hyperpigmentation • Poikiloderma

Stiff skin syndrome Progeria Diabetic cheiroarthropathy Eosinophilic fasciitis Winchester syndrome Metabolic diseases (mucopolysaccharidoses, Niemann–Pick, phenylketonuria)

both activity (erythema, new or larger lesion, increased skin thickness), and damage (hyperpigmentation, telangiectasias, skin thickness).114-116 The modified Localized Scleroderma Severity Index (mLoSSI)115 and Modified Skin Score (MSS)116 divide the body into multiple anatomic sites for scoring. These measures are easy to use, but they are limited by their subjective assessments, arbitrary scoring weights, and possible limited sensitivity for evaluating activity, because both activity and damage features are combined. Evaluation of additional features, such as lesion warmth, blue or violaceous color, and waxy white to yellow lesions,117 and use of a weighted clinical activity measure118 may improve activity assessment. The Computerized Skin Score (CSS) is a quantitative method that longitudinally evaluates change in lesion size, accounting for changes related to normal growth.119,120 This method focuses on monitoring one lesion, and is limited by cost and size of tracing film, and sometimes site of involvement. Several imaging techniques have been used to evaluate LS. Infrared thermography (IT) has high sensitivity for detecting higher surface temperature in active versus inactive lesions, but is limited by low specificity for facial, scalp, and lesions with marked atrophy of the underlying soft tissue.121 Laser Doppler flowmetry (LDF) and laser Doppler imaging (LDI) assess dermal blood flow and were found to have similar sensitivity and better specificity than IT for identifying active versus inactive lesions.122,123 Scanning LDI has the advantage over LDF of being able to evaluate a much larger anatomic area and does not require direct skin contact; this latter feature eliminates a major cause for LDF reading variation.123,124 IT, LDF, and LDI all require patient acclimatization in a temperature-controlled room prior to imaging. Several adult studies have used high-frequency ultrasound as an outcome measure as it can monitor changes in echogenicity and thickness related to initial edema and later sclerosis.125-127 Combined histology and sonographic studies have found a range of dermal echogenicity patterns to be associated with active disease.125,128,129 A pediatric study found hyperechogenicity in the dermis, hypodermis, and muscle to be associated with activity.130 Increased color Doppler signal (hyperemia) was also associated with activity in pediatric and adult patients,128,130 similar to the increased dermal blood flow detected by LDF/LDI and increased surface temperature detected by IT. The

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SECTION THREE  Systemic Connective Tissue Diseases

primary limitation of ultrasound is that it is operator dependent, so training is required to ensure accurate and reliable studies. In addition, because sonographic features vary across sites and between subjects, images of the lesion must be compared to those from a control site, ideally the unaffected contralateral site.131,132 Patients with neurological symptoms often have abnormal neuroimaging studies,75 and it is recommended that those with craniofacial LS and neurological symptoms have an MRI with gadolinium.75 The most common computed tomography (CT) abnormalities are cerebral calcifications, skin/skull atrophy, and cortical depression.75 The most common MRI abnormalities are white matter hyperintensities, abnormal gyral pattern, blurring of gray-white matter, and cerebral atrophy.75 Brain biopsies have shown inflammation including vasculitis, and gliosis, sclerosis, and abnormal and ectatic blood vessels.32,75 Imaging abnormalities have also been found in asymptomatic LS patients, and there is evidence that subclinical neurological disease may be present in many.32,72,133 However, as most patients do not develop overt neurological disease, it is not clear if extensive evaluation of asymptomatic patients is appropriate.75 MRI has identified many musculoskeletal abnormalities in LS, including fascial thickening and enhancement, articular synovitis, tenosynovitis, perifascial enhancement, myositis, and enthesitis.134 Patients with pansclerotic morphea can show bone marrow involvement resembling osteomyelitis.134,135 MRI use is limited by cost and the need for sedation in young children.

TREATMENT OF LOCALIZED SCLERODERMA Medical: Topical, Systemic There are no established guidelines for LS treatment, and many different treatment strategies have been used. Pediatric rheumatologists favor systemic immunosuppressant treatment for patients with moderate to severe disease, which includes most patients except those with circumscribed superficial morphea.136 Dermatologists favor topical agents and phototherapy but also support the use of systemic immunosuppressants for patients with severe involvement.48 Superficial circumscribed morphea commonly causes only minimal permanent skin changes, so therapy primarily consists of topical agents such as topical glucocorticoids, and vitamin D or its analogs.114 More significant circumscribed morphea lesions may benefit from other immunomodulators such as tacrolimus 0.1% ointment or imiquimod, both of which have been evaluated in trials.137,138 There is excellent evidence supporting use of methotrexate (MTX) for moderate to severe disease. Retrospective case series of juvenile LS patients have reported improvement in 74% to 100% of those treated with MTX or a combination of MTX and corticosteroids.139-143 A 12-month randomized placebo-controlled trial showed that MTXtreated patients (15 mg/m2/week, maximum 20 mg) achieved better clinical improvement and had a 2.8-fold lower flare rate than placebotreated patients; all patients had an initial 4-month course of prednisone (1 mg/kg/day, maximum 50 mg per day, for 3 months and then tapered off).120 Side effects were mild and did not lead to withdrawal of any patient from the trial. Corticosteroids have primarily been evaluated in conjunction with MTX, as corticosteroid treatment alone has not been found to provide sustained benefit.144,145 There is no consensus on corticosteroid or MTX regimens, with enormous variation in route of administration, dose, and duration of treatment.136 CARRA developed standardized treatment regimens based upon best available evidence and current North American treatment practices.117 The recommended MTX dose is 1 mg/m2/week (maximum 25 mg) administered subcutaneously. The MTX-based standardized regimens are: (a) MTX alone, (b) MTX plus

oral corticosteroids (2 mg/kg/day, maximum 60 mg, tapered to 1 mg/ kg/day by 4 weeks, and then tapered off by 1 year), and (c) MTX plus intravenous corticosteroids (methylprednisolone, 30 mg/kg/dose, maximum 1 gram; administered either 3 consecutive days per month for 3 months, or for 12 weekly doses).117 The optimal duration of treatment is not known. Despite mean MTX treatment durations of 27.5 to 36 months,139,143,145 flares occurred in 15.4% to 44% of patients141,143,145 at a mean of 4 to 20.4 months off treatment.140-143,145,146 Possible risk factors for flares include a relapsing course in the first 2 years of treatment, longer follow-up time, and linear subtype.141,143,145 Mirsky et al. identified an older age at disease onset (mean 9.25 years versus 7.08 years) as another possible risk factor, whereas Weibel et al. found a younger age of onset associated with risk of flare or relapse (mean 3.3 years versus 5.3 years).141,143 Most children who flare will respond to re-treatment, sometimes with escalation of MTX dose.141,143,145,147 Mycophenolate mofetil has been helpful for some patients who are steroid dependent, do not tolerate MTX, or have an inadequate response to MTX; it can be used either alone or in combination with MTX.148 The CARRA standardized treatment plans recommend dosing according to the U.S. Food and Drug Administration recommendations for pediatric renal disease (600 mg twice a day for patients less than 1.25 m2; 750 mg twice a day for patients 1.25 m2 to 1.5 m2; and 1000 mg twice a day for patients greater than 1.5 m2).97 Biological agents are also being considered as a treatment option for more difficult patients.61,149-151

Phototherapy, Surgical, and Other Treatment and Care Phototherapy has been found to have both antifibrotic and immunosuppressive effects, increasing the expression of collagenases (metalloproteinases), decreasing collagen synthesis and proinflammatory cytokines, and causing T-cell apoptosis.152,153 Many phototherapy regimens have been found to be effective for LS, including narrow band ultraviolet B (UVB) and ultraviolet A1 (UVA1) at low, medium, or high doses, with most studies being open label trials that evaluated changes in skin thickness.152-155 Several open studies including pediatric patients have reported that psoralen UVA (PUVA) bath photochemotherapy is effective in reducing skin hardness in LS.156-158 Although UVA1 has greater skin depth penetration than UVB, it only penetrates to the hypodermis and is not recommended for patients with deeper tissue or extracutaneous involvement.152 The use of phototherapy in children is tempered by concern about potential long-term side effects such as carcinogenesis and skin aging.153 For some patients with severe contractures, options such as ablative fractional laser treatment or surgical reconstruction or correction may be helpful.159,160 Flashlamp pulsed dye laser treatment was reported to improve clinical and histological features of circumscribed morphea lesions that had failed prior treatment. Patients received 7.5 to 8.5 J/cm2 fluence every 2 weeks for an average of eight sessions.161 Patients with significant skin involvement should have physical or occupational therapy directed at counteracting the development of flexion contractures. Moisturizers are recommended to improve xerosis and increase suppleness of the sclerotic areas. Patients with muscle spasm or abnormal movements may benefit from botulinum toxin injection. Botulinum toxin injection into the scalene muscle relieved thoracic outlet syndrome in a patient with linear scleroderma extending from her arm to her trunk, and relieved facial hemidystonia and myokymia in two patients with ECDS.162-164 Different surgical strategies have been used to correct atrophy and other deformities associated with ECDS/PRS, including autologous fat injections, Medpor implants, bone paste cranioplasty, and free groin flap, with good outcomes reported.165,166 Flare of disease following

CHAPTER 28  Localized Scleroderma surgery has been reported,14 and surgery should ideally only be considered when the disease is inactive, and possibly when growth is complete.

Treatment of Pansclerotic Morphea Treatment of children with pansclerotic morphea is challenging. These patients have deep, extensive, and rapidly progressive disease that often fails to respond to treatment with MTX, corticosteroids, and other immunosuppressive medications including cyclophosphamide.5,21,167,168 Patients often develop problematic soft-tissue calcifications and ulcerations, secondary osteoporosis, destructive arthritis, and severe flexion contractures that cause profound disability.5,21 Some pansclerotic morphea patients may benefit from photochemotherapy, combinations of systemic immunosuppressive medications and photochemotherapy, or antithymocyte globulin and cyclosporine.168-170 For very severe pansclerotic cases, autologous stem-cell transplantation may be considered. Patients with refractory ulcers from pansclerotic morphea or bullous morphea may benefit from N-acetylcysteine, bosentan, or sildenafil.21,171,172

Treatment of Eosinophilic Fasciitis Both oral and intravenous corticosteroids have been used to treat eosinophilic fasciitis; intravenous administration may be more effective.173 MTX has been found to be helpful for some patients who fail to respond to corticosteroids or who are steroid dependent,28,147 and a combination initial treatment with MTX or mycophenolate mofetil and corticosteroids may help to reduce cumulative corticosteroid dose and morbidity.107 Case studies have reported benefit from intravenous immunoglobulin, infliximab, rituximab, cyclosporine, D-penicillamine, phototherapy, dapsone, and allogeneic stem-cell transplant in patients who have responded poorly to other treatments.174-182

COURSE OF THE DISEASE AND PROGNOSIS The prognosis for most children with LS is good in contrast with those with SSc. Those with pansclerotic morphea have the poorest prognosis because they usually fail to respond to standard treatment and develop severe, extensive atrophy; contractures; and skin ulceration.5,21,183 Deaths are extremely rare, and those deaths are associated with the pansclerotic subtype due to chronic skin ulcer complications (sepsis, squamous cell carcinoma).5,21,184 Progression to SSc is extremely unlikely (1 of 1134 patients).9,14,31,52 LS has been reported to coexist with juvenile idiopathic arthritis, systemic lupus erythematosus, and Sjögren’s syndrome,9,51,185 so the rare association of LS with SSc may represent coexistence rather than progression. Up to 6% of adult SSc patients have been found to have circumscribed morphea lesions.186 The natural history for many LS patients is a self-limited course, with initial worsening and spread of the lesion(s), followed by resolution of activity features, stabilization of damage features, and softening of lesions occurring in half of the patients with circumscribed morphea by 2.7 years after diagnosis, and by 5 to 5.5 years for the patients with generalized, linear, or deep morphea.16 Current practice has improved this time course with a recent incidence study reporting improvement in 65% of patients and disease stabilization in another 18% by 1 year.29 In some patients, active disease persists for decades. One study found that 35% of linear scleroderma patients had active disease after 10 years, which only declined to 20% at 20 years.16 Two recent studies of patients with childhood disease onset found that 28% to 88% continued to have active disease as adults, either as continuous activity or as a relapsing and remitting course.53,54

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Damage occurs frequently. After about 5 years, nearly all linear scleroderma patients were found to have dyspigmentation, cutaneous atrophy, or both.53 Many patients have functional impairment related to limited joint mobility and limb atrophy. Disability was present in 25% to 44% of patients with linear scleroderma or deep morphea.16 Functional limitation was present in 28% to 38% of juvenile LS patients in three recent studies, including an ongoing prospective registry.36,38,53 A study of 27 adult patients with childhood disease onset found that half had permanent damage (75% in those with linear scleroderma).54 The morbidity of patients who have involvement of the face and head may also be underreported, as about half of 205 surveyed PRS patients reported migraine headache, facial pain, and/or eye or vision problems.187 Most adults with eosinophilic fasciitis achieve remission,173 but many children develop persistent cutaneous fibrosis. Risk factors for persistent fibrosis include extensive disease (three to four extremities and trunk involvement) and younger age (younger than 7 years reported in one study, younger than 12 years in another) at diagnosis.92,93 In adults, a delay in diagnosis (more than 6 months) was a risk factor for poorer outcome.173 Two studies in patients with childhood LS did not find any overall impairment in health-related quality of life (HRQOL),188,189 but another found that two thirds of patients with linear scleroderma had dissatisfaction with their appearance.53 Somatic and psychological problems, such as pain, itch, fatigue, or anxiety, occur frequently in adult eosinophilic fasciitis and LS patients, especially those with generalized morphea.190,191 Although improvements in treatment have resulted in earlier induction of disease inactivity for most children with LS, many continue to have recurrent or persistent active disease and functional impairment. More work is needed to identify optimal treatment for achieving sustained remission and preventing severe morbidities to improve the long-term outcome for these children.

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CHAPTER 28  Localized Scleroderma 145. F. Zulian, C. Vallongo, A. Patrizi, et al., A long-term follow-up study of methotrexate in juvenile localized-scleroderma (morphea), J. Am. Acad. Dermatol. 67 (2012) 1151–1156. 148. G. Martini, A. Ramanan, F. Falcini, et al., Successful treatment of severe or methotrexate-resistant juvenile localized scleroderma with mycophenolate mofetil, Rheumatology (Oxford) 48 (2009) 1410–1413. 152. A. Kreuter, UV-A1 phototherapy for sclerotic skin diseases, Arch. Dermatol. 144 (2008) 912–916. 153. N. Fett, V. Werth, Update on morphea. part II. Outcome measures and treatment, J. Am. Acad. Dermatol. 64 (2011) 231–242.

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The entire reference list is available online at www.expertconsult .com.

CHAPTER 28  Localized Scleroderma

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SECTION THREE  Systemic Connective Tissue Diseases

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124. A. Herrick, S. Clark, Quantifying digital vascular disease in patients with primary Raynaud’s phenomenon and systemic sclerosis, Ann. Rheum. Dis. 57 (1998) 70–78. 125. A. Kreuter, T. Gambichler, F. Breuckmann, et al., Pulsed high-dose corticosteroids combined with low-dose methotrexate in severe localized scleroderma, Arch. Dermatol. 141 (2005) 847–852. 126. H. Stege, M. Berneburg, S. Humke, et al., High-dose UVA1 radiation therapy for localized scleroderma, J. Am. Acad. Dermatol. 36 (1997) 938–944. 127. M. El-Zawahry, H. El-Cheweikh, S.-E.-R. Ramadan, et al., Ultrasound biomicroscopy in the diagnosis of skin diseases, Eur. J. Dermatol. 17 (2007) 469–475. 128. X. Wortsman, J. Wortsman, I. Sazunic, L. Carrenño, Activity assessment in morphea using color Doppler ultrasound, J. Am. Acad. Dermatol. 65 (2011) 942–948. 129. K. Nezafati, R. Cayce, J. Susa, et al., 14-MHz ultrasonography as an outcome measure in morphea (localized scleroderma), Arch. Dermatol. 147 (2011) 1112–1115. 130. S.C. Li, M.S. Liebling, K.A. Haines, et al., Initial evaluation of an ultrasound measure for assessing the activity of skin lesions in juvenile localized scleroderma, Arthritis Care Res. 63 (5) (2011) 735–742. 131. K. Hoffman, U. Gerbaulet, S. el-Gammal, P. Altmeyer, 20-MHz B-mode ultrasound in monitoring the course of localized scleroderma (morphea), Acta Derm. Venereol. Suppl. (Stockh) 164 (1991) 3–16. 132. S.C. Li, M.S. Liebling, F.G. Ramji, et al., Sonographic evaluation of pediatric localized scleroderma: preliminary disease assessment measures, Pediatric. Rheumatology. 8 (1) (2010) 14. 133. S. Appenzeller, M. Montenegro, S. San Juan Dertkigil, et al., Neuroimaging findings in scleroderma en coup de sabre, Neurology. 62 (2004) 1585–1589. 134. S. Schanz, G. Fierlbeck, A. Ulmer, et al., Localized scleroderma: MR findings and clinical features, Radiology. 260 (2011) 817–824. 135. E. Muroi, F. Ogawa, T. Yamaoka, et al., Case of localized scleroderma associated with osteomyelitis, J. Dermatol. 37 (2010) 81–84. 136. S. Li, B. Feldman, G. Higgins, et al., Treatment of pediatric localized scleroderma: results of a survey of North American pediatric rheumatologists, J. Rheumatol. 37 (2010) 175–181. 137. E. Kroft, T. Groeneveld, M. Seyger, E.M.G.J. de Jong, Efficacy of topical tacrolimus 0.1% in active plaque morphea, Am. J. Clin. Dermatol. 10 (2009) 181–187. 138. E. Pope, A.S. Doria, M. Theriault, et al., Topical Imiquimod 5% cream for pediatric plaque morphea: a prospective, multiple-baseline, openlabel pilot study, Dermatology. 223 (2011) 363–369. 139. K. Torok, T. Arkachaisri, Methotrexate and corticosteroids in the treatment of localized scleroderma: a standardized prospective longitudinal single-center study, J. Rheumatol. 39 (2012) 286–294. 140. P. Fitch, P. Rettig, J. Burnham, et al., Treatment of pediatric localized scleroderma with methotrexate, J. Rheumatol. 33 (2006) 609–614. 141. L. Mirsky, A. Chakkittakandiyil, R. Laxer, et al., Relapse after systemic treatment in paediatric morphoea, Br. J. Dermatol. 166 (2011) 443–445. 142. Y. Uziel, B. Feldman, B. Krafchik, et al., Methotrexate and corticosteroid therapy for pediatric localized scleroderma, J. Pediatr. 136 (2000) 91–95. 143. L. Weibel, M. Sampaio, M. Visentin, et al., Evaluation of methotrexate and corticosteroids for the treatment of localized scleroderma (morphoea) in children, Br. J. Dermatol. 155 (2006) 1013–1020. 144. P. Joly, N. Bamberger, B. Crickx, S. Belaich, Treatment of severe forms of localized scleroderma with oral corticosteroids: follow-up study on 17 patients, Arch. Dermatol. 130 (1994) 663–664. 145. F. Zulian, C. Vallongo, A. Patrizi, et al., A long-term follow-up study of methotrexate in juvenile localized-scleroderma (morphea), J. Am. Acad. Dermatol. 67 (2012) 1151–1156. 146. D. Cox, G. O’Regan, S. Collins, et al., Juvenile localised scleroderma: a retrospective review of response to systemic treatment, Ir. J. Med. Sci. 177 (2008) 343–346. 147. E. Kroft, M. Creemers, F. Van Den Hoogen, et al., Effectiveness, sideeffects and period of remission after treatment with methotrexate in localized scleroderma and related sclerotic skin diseases: an inception cohort study, Br. J. Dermatol. 160 (2009) 1075–1082.

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SECTION THREE  Systemic Connective Tissue Diseases

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