Scleroderma refers to hard skin that develops because of an excessive accumulation of collagen. 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.
Addison is credited with describing areas of skin hardness that he called keloids in 1854. 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. Parry–Romberg syndrome was described by Parry in 1825 and Romberg in 1846. Eulenburg provided the name progressive facial hemiatrophy for this subtype in 1871. The first reported case of disabling pansclerotic morphea may have been that of Roudinesco and Vallery-Radot in 1923.
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. 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, a revision of the classification was developed by the Pediatric Rheumatology European Society (PRes). 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 circumscribed morphea of the PRes classification. 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.
|(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.|
|(b) Deep||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.|
|(2) Linear scleroderma||(a) Trunk/limbs||Linear induration involving dermis, subcutaneous tissue, and sometimes muscle and underlying bone, and affecting the limbs and/or the trunk.|
|(b) Head||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.|
|(3) Generalized morphea||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)|
|(4) Pansclerotic morphea||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.|
|(5) Mixed morphea||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])|
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. These lesions can develop hypopigmentation or hyperpigmentation, and primarily affect the trunk.
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.
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. 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. 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 that may occur with or without ECDS ( 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. 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 full-thickness 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. Skin tightness may lead to chronic extensive ulcers with a potential for development of squamous cell carcinoma.
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.
Several skin disorders can precede, coexist, or follow LS.
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 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.
Atrophoderma of Pasini and Pierini is characterized by asymptomatic hyperpigmented, atrophic patches, with well-demarcated, “cliff-drop” 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.
Eosinophilic fasciitis is a rare presentation of primarily fascial involvement with hypergammaglobulinemia, eosinophilia, and high inflammatory markers. 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.
LS is rare, with an estimated incidence of 0.34 to 2.7 cases per 100,000 per year. It appears to be more prevalent in the white population (73% to 82%). 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. The mean age of onset ranges from 6.4 to 10.5 years, and median age from 6.1 to 8.1 years. The female-to-male ratio in children is 1.7-3.7:1, lower than that reported for adults (2.6-7:1). No significant difference in age of onset or sex ratio has been found between subtypes for children.
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. 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. Pansclerotic morphea is extremely rare, with only 5 pansclerotic morphea patients reported in more than 1100 juvenile LS patients.
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%), although one study reported a distribution of 13.2% circumscribed morphea, 52.6% generalized morphea, and 21.7% linear scleroderma. Pansclerotic morphea is also extremely rare in adults.
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, and in over 30% of LS patients in the CARRA registry, a diagnosis was not made for 5 or more years.
Etiology and Pathogenesis
The etiology and pathogenesis of LS are not completely understood, but they seem to share many similarities with SSc. A recent gene 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. A complex interplay of genetic predisposition, autoimmunity, and environmental factors leads to local inflammation and ultimately increased collagen synthesis and deposition in the skin. 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. 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. 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. Patients with LS have elevated serum levels of B-cell activating factors belonging to the transforming growth factor (TGF) family. 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. In one study, the elevated serum levels of TGF correlated with the severity of LS and the presence of antihistone antibodies. Milder cases of LS, such as circumscribed morphea, have levels of TGF-β1 similar to those of healthy controls. The increased production of collagen is further augmented by the decrease in the enzymatic degradation of collagen due to inhibition of matrix metalloproteinases (MMPs).
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. It is estimated that 5% to 10% of patients with LS have other autoimmune diseases. The frequency of a concurrent autoimmune disease is higher in adults (30%). 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, 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. A family history of autoimmune conditions is present in 11% to 24% of cases.
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.
An environmental factor, including medication, infection, or trauma may be the initiating event in some cases of LS. Some medications (bisoprolol, bleomycin, bromocriptine, carbidopa, d-penicillamine, and ergot) have produced scleroderma-like lesions. Recent studies report the association of anti–TNF-α medications with onset of LS although these agents have also been used to treat LS. 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. 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.
Typical LS lesions have been reported after local contusion; injection with aluminum-absorbed allergen extracts for allergy desensitization, mepivacaine, pentazocine, vaccinations, vitamin B 12 , or vitamin K 1 ; and radiation treatment. A preceding history of trauma at the lesion site was reported in 23% to 35.7% of linear scleroderma patients, and 11.8% of circumscribed morphea patients. 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 onset ; there may be a higher frequency of preceding trauma in patients with Parry–Romberg Syndrome. Trauma and vigorous exercise may also be inciting events for some cases of eosinophilic fasciitis.
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. Rarely, LS is evident at birth as areas of faint violaceous discoloration or atrophy without epidermal changes. The skin discoloration can be easily mistaken for a nevus flammeus or port-wine stain, 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. 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) ( 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 thickening ( Fig. 28-6 ).
More than 20% of juvenile LS patients have extracutaneous manifestations, including musculoskeletal, neurological, vascular, ocular, and gastrointestinal involvement. Extracutaneous manifestations can occur in any subtype, with risk for their development not associated with age of disease onset or disease duration. Subtype and lesion location influence the type of extracutaneous manifestation: growth defects (undergrowth) of extremities, trunk, and face/head are associated with linear scleroderma ; and neurological, oral, and ocular problems are associated with linear scleroderma of the head. Joint involvement is associated with linear lesions of extremities, and with pansclerotic, generalized, and deep morphea. 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. Between 4% and 9% of patients have multiple extracutaneous manifestations, with the risk higher in patients with neurological or ocular involvement.
Musculoskeletal problems include arthralgia, arthritis, limited range of motion, contractures, and scoliosis. Oligoarticular or polyarticular arthritis has been reported in 12% of childhood-onset LS patients. 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. 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, and patients with PRS can have severe facial hemiatrophy ( Fig. 28-4 ).
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. Seizures include absence, complex partial, generalized tonic clonic, and status epilepticus, and can be refractory to treatment. 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.
Ocular involvement has been found in 2.1% to 6% of children with LS. The most common ocular complications are fibrotic changes in eyelids, eyelashes, or lacrimal gland and anterior segment inflammation (uveitis, episcleritis). Many other ocular and vision problems have been reported, including hemianopsia, diplopia, ptosis, keratitis, strabismus, acquired glaucoma, enophthalmos, orbital myositis, pupillary mydriasis, and papilledema. 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. These children are at risk for delayed permanent tooth eruption, root resorption and underdevelopment, impaired mandibular movement, and masticatory contractions or spasms. Hemiatrophy of the tongue may occur in half of the children with PRS.
Gastrointestinal, pulmonary, cardiac, and renal problems are uncommon in most patients with LS (1% to 2.6%) and rarely life-threatening. The most common gastrointestinal problem is gastroesophageal reflux. More children with LS may have asymptomatic esophageal abnormalities. 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 tests Conduction abnormalities including ventricular premature beats and right bundle branch block have been found in LS. A 10-year prospective study found children with LS developed asymptomatic hypertension and diastolic dysfunction at a significantly higher frequency than healthy controls. 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.
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 bound-down, rock-hard consistency. Joint contractures and myositis are common in children, and 25% to 44% have polyarthritis. Up to 29% may have LS lesions of eosinophilic fasciitis.
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. Histiocytes may surround individual collagen fibers, creating a “floating” appearance. ECDS variant may present with more prominent vacuolar degeneration at the dermoepidermal junction. Goh et al. described a pattern of perineural lymphoplasmacytic infiltration in alopecia occurring in an ECDS lesion, 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. 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.
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. The sparing of the papillary dermis, marked inflammatory infiltrate, and presence of eosinophils should allow pathological differentiation from classical LS lesions.
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. However, in LS the inflammatory infiltrate is more intense and often found at the dermal–subcutaneous junction, a site not involved in SSc inflammation. 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.
The manifestations of localized scleroderma are easily overlooked or attributed to other etiologies, particularly in the early stages ( Table 28-2 ). Early recognition is important because it allows intervention 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. 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.
|INFLAMMATORY PHASE||INFILTRATIVE (INDURATED) PHASE||INACTIVE (“DAMAGE”) PHASE|
|PRIMARILY SKIN||PRIMARILY JOINTS|
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.
Patients with eosinophilic fasciitis usually have an elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), eosinophilia, and hypergammaglobulinemia. Some have elevated muscle enzymes, with aldolase more commonly elevated than creatine kinase (CK). The same abnormalities are infrequently found in children with LS, primarily in those with deeper, more extensive disease, such as pansclerotic morphea, and in some children with active linear scleroderma or generalized morphea. For both eosinophilic fasciitis and LS, abnormal tests tend to normalize as the disease becomes less active. In pediatric eosinophilic fasciitis, unlike adult disease, hematological abnormalities are uncommon.
Many autoantibodies are found in LS. ANA positivity ranged from 42.3% to 50% in three large juvenile LS cohorts. ANA was associated with extracutaneous manifestations in one study, and with more extensive skin involvement in linear scleroderma in another. Rheumatoid factor (RF) is found in 15.9% to 26% of LS patients, more frequently in those with arthritis or other extracutaneous manifestations. 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. Single-stranded DNA antibodies have also been associated with muscle disease. Antiphospholipid antibodies (anticardiolipin, lupus anticoagulant, anti-phosphatidylserine–prothrombin complex) have been found most commonly in generalized morphea. Only rarely have patients had thromboembolic events, most commonly with anti-phosphatidylserine–prothrombin complex antibodies. 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). 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.
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.
Several semiquantitative clinical scoring measures have been used to evaluate patient response during treatment. Current measures score both activity (erythema, new or larger lesion, increased skin thickness), and damage (hyperpigmentation, telangiectasias, skin thickness). The modified Localized Scleroderma Severity Index (mLoSSI) and Modified Skin Score (MSS) 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, and use of a weighted clinical activity measure 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. 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. 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. 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. 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. Combined histology and sonographic studies have found a range of dermal echogenicity patterns to be associated with active disease. A pediatric study found hyperechogenicity in the dermis, hypodermis, and muscle to be associated with activity. Increased color Doppler signal (hyperemia) was also associated with activity in pediatric and adult patients, similar to the increased dermal blood flow detected by LDF/LDI and increased surface temperature detected by IT. The 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.
Patients with neurological symptoms often have abnormal neuroimaging studies, and it is recommended that those with craniofacial LS and neurological symptoms have an MRI with gadolinium. The most common computed tomography (CT) abnormalities are cerebral calcifications, skin/skull atrophy, and cortical depression. The most common MRI abnormalities are white matter hyperintensities, abnormal gyral pattern, blurring of gray-white matter, and cerebral atrophy. Brain biopsies have shown inflammation including vasculitis, and gliosis, sclerosis, and abnormal and ectatic blood vessels. Imaging abnormalities have also been found in asymptomatic LS patients, and there is evidence that subclinical neurological disease may be present in many. However, as most patients do not develop overt neurological disease, it is not clear if extensive evaluation of asymptomatic patients is appropriate.
MRI has identified many musculoskeletal abnormalities in LS, including fascial thickening and enhancement, articular synovitis, tenosynovitis, perifascial enhancement, myositis, and enthesitis. Patients with pansclerotic morphea can show bone marrow involvement resembling osteomyelitis. MRI use is limited by cost and the need for sedation in young children.