Localized Scleroderma and Eosinophilic Fasciitis

Historical Review

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 LS, including sclerodermie en coup de sabre and the atrophy associated with linear forms. Parry–Romberg syndrome, characterized by facial hemiatrophy, 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. Eosinophilic fasciitis was first reported by Shulman in 1975.

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) that 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 added mixed subtype that includes a combination of subtypes ( 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/limb 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.

Circumscribed morphea (CM) refers to oval or round shape lesions that are centrally indurated with a waxy, ivory color and a violaceous rim ( Fig. 28.1 ). There are two depths of involvement. Superficial CM 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 CM affects the deeper dermis and subcutaneous tissues, resulting in tight and bound down skin in the acute phase and persistent fibrosis plus or minus deep dermal and subcutaneous atrophy in the burnt out phase. CM 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 CM that presents as multiple small (2 to 10 mm), initially erythematous or violaceous, and later yellow-whitish sclerotic lesions with a shiny or depressed surface. ^, These lesions can develop hypo- or hyperpigmentation and primarily affect the trunk. Other clinical presentation of CM are nodular or keloidal morphea, which consists of firm nodules, akin to keloids, either isolated or confluent lesions forming a plaque.

Generalized morphea (GM) ( Fig. 28.1B ) consists of four or more individual lesions, typically with a diameter larger than 3 cm, involving at least two of seven anatomical sites (head-neck, right upper extremity, left upper extremity, right lower extremity, left lower extremity, anterior trunk, posterior trunk). Unilateral GM 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, band-like lesions that typically involve upper or lower extremities ^{, ,} and the face. The lesions may not appear contiguous at the outset, but 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 and bound down with various degrees of involvement of dermis, subcutaneous tissue, and underlying muscle, joints, and bone ( Fig. 28.2 ).

Linear lesions of the face or scalp are called the en coup de sabre variety (ECDS) because of 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 face and 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, permanent facial asymmetry and disfigurement. Oral involvement may occur, potentially affecting all structures, including lips, gingiva, and bony structures, resulting in various degrees of atrophy and misalignment ( Fig. 28.5 ).

Disabling pansclerotic morphea (DPM), extremely rare in pediatric populations, is the most severe subtype of LS consisting of widespread, full-thickness skin involvement and commonly involves underlying muscle and bone. Lesions start on the extremities with the exception of fingers and toes, which are usually spared, and progress to involve all anatomical areas, including the face. Skin tightness causes contractures and may lead to chronic extensive ulcers with a potential for auto-amputation of the affected limb and development of squamous cell carcinoma. ^,

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

Associated Conditions

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 CM may be difficult. Genital involvement creates an “hour-glass” appearance resulting from the discoloration surrounding the vaginal and perianal area. It is usually accompanied by significant pruritus and/or burning sensation as a result of fissuring. Occasionally hemorrhagic blistering may develop, raising concern about child abuse. There is a high prevalence of lichen sclerosus et atrophicus in patients with CM and CM.

Atrophoderma of Pasini and Pierini is characterized by asymptomatic hyperpigmented, atrophic patches with well-demarcated “cliff-drop” borders ( Fig. 28.6B ). These lesions, primarily seen on the trunk, lack the typical inflammatory changes of CM and may represent the “burned-out” phase of deep morphea.

Bullous morphea is extremely rare, occurring with most subtypes, including typical CM. The pathogenesis of the bullous lesions is not well understood; local lymphatic obstruction from collagen deposition may play a role. ^,

Eosinophilic fasciitis (EF) is a rare presentation of primarily fascial inflammation with hypergammaglobulinemia, eosinophilia, and high inflammatory markers. ^, EF can present with painful swelling with progressive induration and thickening of the skin creating a “peau d’orange” appearance, but in a number of pediatric patients, skin findings are minimal or absent at presentation. EF tends to involve extremities and often the hands and feet in children. The limited anatomical involvement of EF, with sparing of the face and trunk, high peripheral blood eosinophil counts, and thickened and inflamed fascia allow for differentiation from DPM, although the distinction is not always possible.

Epidemiology

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 2010 to 2014 US registry of over 8000 pediatric rheumatology patients (Childhood Arthritis Rheumatology Research Alliance [CARRA] Legacy registry), there were about 17-fold fewer patients with LS than with juvenile idiopathic arthritis, and about threefold fewer patients with LS than with systemic lupus erythematosus. ^,

Most patients with pediatric LS present 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 1.7:1 to 3.7:1, lower than that reported for adults (2.6:1 to 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. Studies report subtype frequencies of 41.8% to 66.7% for linear scleroderma, 15% to 36.8% for CM, 3% to 23% for mixed morphea, and 6.6% to 11% for GM. ^{, , , , ,} Pansclerotic morphea is extremely rare, with only 5 patients with pansclerotic morphea reported among more than 1100 patients with juvenile LS (<0.5%). ^{, , ,} EF is also very rare; in the largest reported juvenile LS cohort, only 10 of the 750 patients had EF (1.3%).

Adults have a different subtype distribution, with CM the most common presentation (43.9% to 69%), followed by GM (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% CM, 52.6% GM, 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 have reported a mean time between initial symptom and diagnosis of 11 to 21.6 “months”. ^{, , ,} In the recent CARRA Legacy registry, there was a delay of 2 years or more before juvenile LS diagnosis for 17% of the patients.

Etiology and Pathogenesis

The etiology and pathogenesis of LS are still not well understood. LS shares some processes and mechanisms with SSc, with skin biopsies often indistinguishable. A genome-wide gene expression analysis of adult skin samples identified a shared inflammatory pattern for LS and SSc patients (both diffuse and limited), with additional unique patterns identified for SSc. For both diseases, a combination of genetic predisposition, autoimmunity, and environmental factors are thought to trigger local inflammation that leads to persistent increased collagen synthesis and deposition in the skin. The proposed initiating event in SSc is endothelial cell injury resulting in release of cell mediators, upregulation of cell adhesion molecules, and activation and recruitment of immune cells, which can then lead to endothelial cell apoptosis, tissue ischemia, fibroblast activation, vascular remodeling, and fibrosis. Vascular injury has also been postulated to be a key event for LS.

Identified human leukocyte antigen (HLA) associations support an autoimmune pathogenesis for LS, as do the frequent occurrence of autoantibodies, concurrent autoimmune conditions, and family history of autoimmune conditions. The strongest identified HLA associations were with DRB1∗0404 for class II and HLA-B∗37 for class I, with most of the identified associations different from those identified for adult SSc. Antinuclear antibody (ANA) positivity has been found in 26% to 59 % of juvenile LS patients, with the two largest cohorts reporting 42% to 48% positivity. ^{, , , , , , ,} Approximately 5% to 10% of LS patients have other autoimmune diseases including vitiligo, psoriasis, inflammatory arthritis, systemic lupus erythematosus, and others. ^{, , ,} Longer disease durations are associated with higher frequencies of concurrent autoimmune disease (17% to 26%). ^, A family history of autoimmune conditions is also associated with LS in 11% to 24% of patients. ^{, , ,}

Potential environmental triggers for LS include trauma, intramuscular injections, medications, radiation, pregnancy, and infection. The causality of traumatic events is often difficult to determine because minor trauma is so common in children. Two older studies reported 25% to 35.7% of linear scleroderma patients and 22.8% of CM patients had a history of local trauma preceding the appearance of the lesion. ^, More recently, 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. Typical LS lesions have been reported after injections with aluminum-absorbed allergen extracts for allergy desensitization, mepivacaine, pentazocine, vaccinations, vitamin B ₁₂ , or vitamin K _1. Trauma preceding the development of PRS has also been reported.

Several medications have been associated with LS-like lesions including bisoprolol, bleomycin, bromocriptine, carbidopa, d-penicillamine, ergot, and tumor necrosis factor (TNF) inhibitors. ^, LS is a known rare complication of radiotherapy that may be related to the high production of some cytokines (interleukin [IL]-4, IL-5, transforming growth factor [TGF]-β) induced by therapy. Pregnancy has also been associated with LS, with one woman developing LS lesions during pregnancy, which then spontaneously resolved shortly after delivery. Microchimerism related to fetal cells invading maternal tissue has been suggested as a possible disease trigger similar to graft-versus-host, and chimeric cells consisting of a predominance of dendritic cells have been found in LS lesions. Borrelia species have been evaluated as a potential etiology in many studies. These studies, which include polymerase chain reaction (PCR) analysis of lesions, have not supported causality between Borrelia and LS. ^,

Triggers have also been reported for EF, with muscle trauma related to intense exercise or direct injury reported in 30% to 46% of adult patients before onset. In pediatric patients, an association with trauma is less common, and nonspecific infections may precede EF onset. Medications (statins, phenytoin, subcutaneous heparin), radiotherapy, and burns have also been associated with EF in adults. ^{, ,} A toxin contained in some lots of L-tryptophan was implicated in a large epidemic of eosinophilia-myalgia syndrome, a disease similar to EF and LS. ^, Adult EF is also associated with autoimmune diseases including Hashimoto thyroiditis, lupus, vasculitis, idiopathic thrombocytopenic purpura, and Sjögren syndrome, as well as hematological disorders, neoplasms, and infections.

Many cytokines and chemokines have been found to be elevated in LS, including IL-1β, IL-2, IL-4, IL-6, IL-8, IL-12, IL-13, IL-17A, TNF-α, TGF-β1 and TGF-β2, interferon (IFN)-γ, IP-10, membrane cofactor protein (MCP)-1, and granulocyte-macrophage colony-stimulating factor (GM-CSF). T cells have been identified in LS skin lesions and in a brain biopsy of a patient with craniofacial LS, with the T cells in skin lesions identified as predominantly T helper lymphocytes. Flow cytometry studies in juvenile LS patients have also identified a preponderance of T helper (Th) cells, as well as a reduction in functional regulatory T cells. Recent studies have shown a Th1 proinflammatory, IFN-γ pattern in the blood and LS skin lesions during the active stage, while a lower level of Th17 related IL-17A has been found in skin lesions. Th1 cells were also identified in the inflammatory infiltrate of skin lesions. Among the IFN-γ–associated genes, IP10 , CXCL9 , and CXCL10 show potential promise as biomarkers associated with disease activity. ^{, ,} The profibrotic Th2 cells and cytokines likely play a more major role in the later fibrotic stages.

Patients with LS also have elevated serum levels of B-cell activating factors belonging to the TGF family. Upregulation of TGF-α and -β induces production of platelet-derived growth factor (PDGF); connective tissue growth factor (CTGF); IL- 2, IL-4, IL-6, IL-8, and IL-13; and soluble receptors IL-2R and IL-6R, resulting in increased mitogenic activity of fibroblasts and production of collagen. ^, The increased production of collagen is further augmented by the decrease in the enzymatic degradation of collagen resulting from inhibition of matrix metalloproteinases (MMP).

In EF, immune derangements include hypergammaglobulinemia, eosinophilia, and eosinophil and C3 deposition in the fascia. Peripheral blood mononuclear cells have been found capable of producing more IFN-γ, IL-5, and IL-10. Unlike LS, there is a predominance of CD8 ⁺ rather than CD4 ⁺ T lymphocytes in the muscle and fascia infiltrates, suggesting a cytotoxic-mediated immune response.

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 present with 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 and can also present with generalized lymphadenopathy. ^, In some patients, arthritis or a neurological problem (e.g., seizures, headaches, or focal deficits) precedes the development of skin lesions. ^, Rarely, LS presents 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. 28.1A –D). 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 ). There is agreement among clinicians that a red or violaceous rim, increased local warmth, raised borders, and dermal thickening are signs of disease activity. A recent prospective study identified erythema, disease extension, violaceous color (i.e., lilac ring), waxy white or yellow color, and tactile warmth as specific signs of disease activity that correlate with physician assessment of activity. Waxy whit e or yellow refers to lesions that have a smooth surface associated with skin thickening and a white or yellow color ( Fig. 28.1 ). Skin thickening is not specific for activity as it is associated with both active and inactive lesions; however in active lesions, the level of skin thickening does track with activity. Damage features include postinflammatory hyperpigmentation, atrophy of epidermis (shiny skin with visible venous pattern), dermis (loss of hair follicles and adnexal structures and cliff-drop atrophy), subcutaneous tissue (loss of fat) ( Fig. 28.6 ), and progressive skin thickening ( Fig. 28.7 ).

Approximately 20% to 70% of patients with patients with juvenile LS have been reported to have extracutaneous (EC) manifestations, with higher frequencies reported in prospective studies. ^{, , ,} EC involvement can occur in any subtype, and development has not been associated with age of disease onset or disease duration. ^{, , , ,} The most common EC manifestations are musculoskeletal, neurological, ocular, and oral. Subtype and lesion location influence the type of EC manifestation, with growth defects (undergrowth) of extremities, trunk, and face/head more common with linear scleroderma of an extremity, ^, and neurological, oral, and ocular problems more commonly associated with linear scleroderma of the head. ^{, ,} Joint involvement is associated with linear lesions of extremities, and with pansclerotic, generalized, and deep morphea. ^{, , ,}

EC manifestations are usually related to the anatomical site of the skin lesion, but involvement remote from the lesions has been reported in greater than or equal to 25% of those with arthritis, neurological, or ocular problems. Seizures, headaches, and arthropathy have all been reported to precede the appearance of skin lesions, sometimes by years. ^{, , ,} Between 4% and 9% of patients have multiple EC manifestations, with the risk higher in patients with neurological or ocular involvement. ^{, , ,}

Musculoskeletal problems are the most common type of EC involvement. Arthralgias have been reported in 12% to 26% of patients, joint contractures or limited range of motion in 18% to 21%, and arthritis in 5% to 20%. ^{, , , ,} Musculoskeletal (MSK) involvement can include the appearance of “dry synovitis,” with painless limitation of joint range of motion and synovium showing thickening associated with fibrosis and sparse inflammatory infiltrate. Muscle involvement includes myositis, myalgia, muscle cramps, atrophy, and weakness, with electromyographs showing myopathy more commonly than a neurogenic pattern. ^{, ,} Other MSK problems include scoliosis and growth defects including limb length differences, angular deformities, and joint deformities. Growth defects may be subtle until the child has a growth spurt, making the asymmetry obvious. Defects can be severely disabling or disfiguring; limb length differences of greater than 11 cm have been reported, with earlier age of disease onset often associated with more significant differences.

MSK problems are a major cause of disability for juvenile LS patients. An earlier study reported that 13 of 15 patients with juvenile LS that had lesions on their extremities had joint limitation, nine of whom required orthopedic surgical correction. In a recent study of 51 children with linear scleroderma, half had orthopedic issues, including joint contracture (45%), limb atrophy (31%), angular deformity (18%), and limb length difference (16%). MSK problems are the norm for patients with pansclerotic morphea who are also at risk for soft-tissue calcifications and secondary osteoporosis. ^, Schoch et al. reported that seven (14%) of their linear scleroderma patients needed surgical intervention, with three requiring multiple procedures to improve function.

Lesions on the head are associated with neurological, ocular, oral, and bone problems. Children with PRS are at risk for developing severe facial hemiatrophy ( Fig. 28.4 ), which may be associated with enophthalmos severe enough to result in ocular torticollis. Neurological involvement has been reported in 4.4% to 10% of children with LS, with a much higher frequency (25% to 50%) in patients who have linear scleroderma of the head (ECDS, PRS). ^{, , ,} Neurological involvement includes seizures and headache (including migraine headaches) and central nervous system imaging abnormalities. ^{, , ,} 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, Rasmussen and other autoimmune encephalitides, demyelinating encephalomyelitis, neuropsychiatric problems, movement disorders, slurred speech, cognitive problems, cavernomas, and central nervous system vasculitis. ^{, , ,}

Ocular involvement has been found in up to 6% of children with LS. ^{, ,} The most common ocular complications are fibrotic changes in eyelids, eyelashes (often lost where lesions cross the eye), 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, orbital pseudotumor, pupillary mydriasis, Adie pupil, papilledema, abnormal retinal vessels, and retinal detachment. ^{, ,}

Defects in growth of the lower third of the face, malocclusion, and paranasal sinus defects occur frequently in children with facial lesions. Hemiatrophy of the tongue may occur in half of the children with PRS. Dental issues include ectopic or delayed tooth eruption, tooth crowding, root deficiencies or resorption, and gingival and periodontal ligament defects. Patients can have impaired mandibular movement and masticatory contractions or spasms.

Gastrointestinal, pulmonary, cardiac, and renal problems are uncommon in most patients with LS (1% to 2.6%) and rarely are 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 can be found to have a restrictive pattern and/or a decreased diffusion capacity for carbon monoxide (DLCO) on pulmonary function tests. ^{, ,} Pansclerotic morphea may be associated with a higher frequency of lung involvement, including decreased DLCO, decreased vital capacity, and fibrosis of lung bases; however, affected patients were asymptomatic. Cardiac 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. ^, One pansclerotic morphea patient had a progressive nonobstructive cardiomyopathy. ^{, ,}

EF, unlike LS, usually presents as acute onset of painful, rapidly progressive symmetrical involvement of the extremities. Among adults, 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; there can be a linear depression along veins (groove sign). ^, Up to half the children may present with bilateral, rapidly progressive, severe joint limitation without obvious skin findings that can lead physicians to suspect juvenile idiopathic arthritis (JIA) rather than EF. A transient angioedema-like presentation has also been reported, with painless swelling and erythema. Contractures can rapidly progress to disability with profound loss of function of hands or legs within weeks. Besides contractures, polyarthritis and myositis are also common. ^{, ,} Over 30% of children also present with visceral involvement including mesenteric lymphadenopathy, hepatomegaly, splenomegaly, and pericardial effusion. Up to 29% may have LS lesions together with or after EF.