Introduction
Background
Morphea, also known as localized scleroderma, is a disorder characterized by excessive collagen deposition leading to thickening of the dermis, subcutaneous tissues, or both. Morphea is classified into plaque, generalized, linear, and deep subtypes according to the clinical presentation and depth of tissue involvement. Unlike systemic sclerosis, morphea lacks features such as sclerodactyly, Raynaud phenomenon, nailfold capillary changes, telangiectasias, or progressive internal organ involvement. Morphea can present with extracutaneous manifestations, including fever, lymphadenopathy, arthralgias, and central nervous system involvement, and laboratory abnormalities, including eosinophilia, polyclonal hypergammaglobulinemia, and positive antinuclear antibodies.1,2,3
Although rare, epidemiologic studies suggest 0.9-5.7% of patients with morphea progress to systemic scleroderma.2 The transition may be marked by the development of Raynaud phenomenon and nailfold capillary changes.
Pathophysiology
Overproduction of collagen by fibroblasts in affected tissues is common to all forms of morphea, although the mechanism by which these fibroblasts are activated is unknown. Proposed factors involved in the pathogenesis of morphea include endothelial cell injury, immunologic (eg, T lymphocyte) and inflammatory activation, and dysregulation of collagen production. An autoimmune component is supported by the frequent presence of autoantibodies in affected individuals, as well as the association of morphea with other autoimmune diseases, including systemic lupus erythematosus, vitiligo, type 1 diabetes, and myasthenia gravis.1,3
Endothelial cell injury is currently thought to be the inciting event in the pathogenesis of morphea. This injury results in increased levels of adhesion molecules (circulating intercellular adhesion molecule-1, vascular cell adhesion molecule 1, and E-selectin) and fibrogenic T-helper 2 cytokines such as interleukin (IL)–4, IL-6, and transforming growth factor-beta (TGF-beta). These cytokines recruit eosinophils, CD4+ T cells, and macrophages, which are present in early morphea lesions and in eosinophilic fasciitis. These cytokines and growth factors also increase fibroblast proliferation and induce synthesis of excess collagen and connective-tissue growth factor. Connective-tissue growth factor is a soluble mediator that enhances and perpetuates the profibrotic effects of TGF-beta. The ultimate result of the endothelial injury and inflammatory cascade is increased collagen and extracellular matrix deposition.4,5,6,7,8
Frequency
United States
The incidence of morphea has been estimated as approximately 25 cases per million population per year. The actual incidence is likely higher because many cases may not come to medical attention. Two thirds of adults with morphea present with plaque-type lesions, with generalized, linear, and deep variants each accounting for approximately 10% of cases. Up to half of all cases of morphea occur in pediatric patients. In this group, linear morphea predominates (two thirds of cases), followed by the plaque (25%) and generalized (5%) subtypes. Of note, as many as half the patients with linear morphea have coexistent plaque-type lesions.
Mortality/Morbidity
Morphea typically has a benign, self-limited course. Survival rates for morphea patients are no different from those of the general population. However, linear and deep morphea subtypes can cause considerable morbidity, especially in children when they interfere with growth. Joint contractures, limb-length discrepancy, and prominent facial atrophy result in substantial disability and deformity in a quarter to half of all patients with linear or deep morphea. Neurologic and ophthalmologic manifestations can also occur in those with craniofacial lesions (eg, en coup de sabre, Parry-Romberg syndrome). Such complications are more common in pediatric cases. Depression and anxiety are prevalent in patients with morphea and correlate with the amount of skin involvement.9
Race
Although morphea occurs in persons of all races, it appears to be more common in whites than in African Americans.
Sex
Women are affected approximately 3 times as often as men for all forms of morphea except the linear subtype, which only has a slight female predominance.
Age
Linear morphea commonly manifests in children and adolescents, with two thirds of cases occurring before age 18 years. Other morphea subtypes have a peak incidence in the third and fourth decades of life.
Clinical
History
Morphea is usually asymptomatic, and the development of lesions is typically insidious. One exception is the acute, painful onset of eosinophilic fasciitis.
Extracutaneous involvement is present in 20% of patients.10 Extracutaneous manifestations are more common in the linear and generalized subtype.
- Arthralgias, usually localized to an affected extremity, may be reported by patients with morphea. Linear and deep lesions can also be associated with arthritis, myalgias, carpal tunnel syndrome, and other peripheral neuropathies.
- Dysphagia (esophageal dysmotility or reflux), dyspnea, and vascular complaints also are reported.
- Patients with craniofacial linear morphea can present with seizures (typically complex partial), headaches, cranial nerve palsies, trigeminal neuralgia, hemiparesis/muscle weakness, eye pain, and visual changes secondary to involvement of the underlying central nervous system.
Physical
Physical findings in morphea are localized to the affected skin and underlying tissues, with varying configurations (eg, oval, linear, ill defined) and depths of involvement in the subtypes. Although subdivision of morphea by subtype is useful with regard to differences in epidemiology, anatomic site, and course of disease, it is important to recognize that continuous clinical and histologic transitions exist among all the variants within the morphea spectrum.
Plaque-type morphea
Plaque-type morphea, as shown in the image below, is the most common and benign morphea subtype.
Inflammatory plaque-type morphea on the abdomen, characterized by induration, erythema, and a surrounding lilac ring.
Plaque-type lesions are characterized as circumscribed, indurated plaques that range from 1 cm to more than 20 cm in diameter. These lesions are relatively superficial, primarily involving the dermis. They often begin as oval-round erythematous to violaceous patches or slightly edematous plaques. In active phases of the disease, a violaceous border (lilac ring) may surround the indurated region. With disease progression, sclerosis develops centrally as the lesions undergo peripheral expansion. Over a period of months to years, the surface becomes smooth, shiny, and ivory in color over time, with loss of hair follicles and sweat glands. Hyperpigmentation often ensues as lesions evolve and eventually involute.
Patients can present with single or multiple plaque-type morphea lesions. Oval plaques on the trunk are often oriented with their long axes in a horizontal direction and typically have an asymmetric distribution. Plaque-type morphea is more common on the trunk (especially the lower aspect) than on the extremities, and the face is usually spared.
Variants of plaque-type morphea are as follows:
- Guttate morphea lesions are multiple and primarily involve the neck and the upper portion of the trunk. The lesions are small (<10 mm in diameter) and superficial, with less induration and a sharply demarcated border. The sclerotic lesions of guttate morphea are typically whitish in color. The clinical appearance may overlap with that of extragenital lichen sclerosus, but true guttate morphea lacks epidermal atrophy and follicular plugging.
- Keloidal (nodular) morphea is a rare variant characterized by nodules resembling keloids in the presence of typical plaque-type morphea.
- Atrophoderma of Pasini and Pierini is thought to represent an abortive form of morphea and resembles "burnt-out" plaque-type lesions. It is typically located on the trunk and is characterized by hyperpigmented, slightly depressed areas with well-defined "cliff-drop" borders and no obvious induration. Similar hyperpigmented patches with minimal induration are seen in persons with superficial morphea, which, unlike atrophoderma of Pasini and Pierini, is characterized histologically by sclerosis of the upper dermis. Superficial morphea favors intertriginous sites such as the axillae and inner thighs.
- Bullous morphea is a rare variant in which tense subepidermal bullae develop overlying plaque-type, linear, or deep morphea lesions. This phenomenon may result from stasis of lymphatic fluid due to the sclerodermatous process or coexisting lichen sclerosus.
Generalized morphea is a more extensive and severe form of plaque-type disease. Generalized morphea occurs when morphea plaques become confluent or multiply and affect a significant portion of 3 or more major anatomical regions, often involving the chest, abdomen, lower back, buttocks, and thighs. The multiple, coalescent lesions of generalized morphea often range from hyperpigmented to silvery. In a rare variant of almost universal morphea, the whole body, from the top of the head to the feet, is involved; unlike diffuse systemic scleroderma, patients lack sclerodactyly, Raynaud phenomenon, nailfold capillary changes, or internal involvement.
Linear morphea
Linear morphea, as shown in the image below, includes the en coup de sabre and Parry-Romberg variants
A hyperpigmented band of linear morphea involving the right part of the trunk and thigh.
Linear morphea often qualifies as deep morphea (albeit in a linear pattern), involving the deep dermis, subcutaneous fat, muscle, bone, and even underlying meninges and brain. Linear morphea features discrete, indurated linear bands that are most often single and are unilateral in 95% of cases. Older lesions may be either atrophic or sclerotic.
Linear morphea most often occurs on the lower extremities, followed in frequency by the upper extremities, frontal portion of the head, and anterior trunk. Many cases of linear morphea following Blaschko lines have been described, although most lesions do not obviously correspond to Blaschko lines.11,12 Linear morphea usually extends along the length of an extremity, but sometimes a band surrounds a limb or finger circumferentially, resembling ainhum (a constriction band that can lead to amputation of a digit). Nail dystrophy may develop when linear lesions involve the nail matrix and in pansclerotic morphea.
Frontoparietal linear morphea, called en coup de sabre, is characterized by a linear, atrophic depression affecting the frontoparietal aspect of the face and scalp, suggestive of a stroke from a sword, as shown in the image below. Paramedian lesions are more common than median lesions. Such lesions may extend deep into underlying tissues. Scalp involvement results in scarring alopecia. Loss of eyebrows and eyelashes can also occur in this variant.
Linear atrophic depression of an en coup de sabre lesion on the right side of the forehead and the frontal part of the scalp.
Parry-Romberg syndrome (progressive hemifacial atrophy) is thought to represent a severe, segmental form of craniofacial linear morphea. Unlike en coup de sabre, the primary abnormality occurs in the subcutaneous fat, muscle, and bone. Although the skin is typically not indurated or bound down, some patients also exhibit primary cutaneous sclerosis reminiscent of en coup de sabre.
Deep morphea
Deep morphea, as seen in the image below, is also referred to as subcutaneous morphea or morphea profunda and primarily involves the subcutaneous fat and underlying structures such as fascia.
Morphea profunda involving the left lower extremity, with thickened, taut, bound-down skin.
Variants of deep morphea include eosinophilic fasciitis and disabling pansclerotic morphea of children.
Deep morphea is characterized by ill-defined, bound-down, sclerotic plaques with a "cobblestone" or "pseudo-cellulite" appearance. The "groove sign" (a depression along the course of a vein, between muscle groups, or both) may be evident later in the course of disease. Distribution of lesions is often symmetric. Deep morphea lesions are frequently hyperpigmented, but, because of the deeper level of inflammation, they lack the other color changes typical of plaque-type morphea.
Eosinophilic fasciitis (Shulman syndrome) involves primarily the fascia and is characterized by an acute onset of symmetric pain and edema of the extremities or trunk, followed by progressive induration with an appearance similar to deep morphea. Eosinophilic fasciitis most often affects the extremities, sparing the fingers and toes; the trunk is occasionally involved.
Disabling pansclerotic morphea of children has generalized involvement that extends throughout the tissues from dermis to bone. It begins on the extensor extremities and progresses to the trunk, flexor extremities, face, and scalp, eventually sparing only the fingertips and toes.
General examination
- Extensive truncal morphea may lead to restricted respiration.
- When linear or deep morphea lesions cross joint lines, they can cause restricted mobility, contractures, and deformity. In children, such lesions can result in growth impairment and severe atrophy of affected limbs.
- Muscle weakness may occur in patients with central nervous system abnormalities related to craniofacial linear morphea and in those with peripheral nerve involvement by morphea on an extremity.13 Signs of carpal tunnel syndrome may be evident in patients with deep morphea affecting the wrist (especially eosinophilic fasciitis).
- Ocular manifestations of craniofacial morphea include ptosis, extraocular muscle dysfunction, anterior uveitis, episcleritis, glaucoma, xerophthalmia, and keratitis.
- Oral findings in patients with craniofacial morphea include altered dentition, malocclusion, and asymmetry of the tongue.
Causes
The cause of morphea is unknown. An autoimmune mechanism is suggested by an increased frequency of autoantibody formation and a higher prevalence of personal and familial autoimmune disease in affected patients.14 The generalized subtype has a higher association with autoimmunity, with a higher frequency of concomitant autoimmune disease, systemic findings, and positive antinuclear antibody findings.3 To date, investigations have not described any consistent etiologic factors. Different morphea subtypes often coexist in the same patient, suggesting that the underlying processes are similar.
- Radiation therapy: Morphea can occur at the site of previous supervoltage radiation therapy for breast cancer and other malignancies, developing from 1 month up to more than 20 years after irradiation.15
- Chimerism: Immature chimeric cells have been found in morphea lesions, suggesting that such nonself cells may lead to an autoimmune phenotype.10
- Infection or vaccination
- Infections, such as Epstein-Barr virus infection, varicella, measles, hepatitis B, and borreliosis, have been reported to precede the onset of morphea and have been proposed as possible triggers.
- The most extensive literature focuses on Borrelia burgdorferi as a possible etiologic agent for morphea. Some studies have detected Borrelia DNA within morphea lesions from a subset of European and Japanese patients (representing Borrelia afzelii and Borrelia garinii rather than B burgdorferi sensu stricto, the predominant subtype in the United States). Studies have shown an increased frequency of B burgdorferi in active morphea lesions by immunohistochemistry16 ; however, to date, this has not been demonstrated in patients from the United States.17,18
- Antibodies to B burgdorferi and high antinuclear antibody titers have been shown to be associated with early-onset morphea.14 Thus, Borrelia -associated early-onset morphea may represent a subset of patients with infection-induced autoimmunity. However, this subset of patients is not reflective of patients with morphea as a whole, because subsequent studies have not found serologic or polymerase chain reaction–based evidence of Borrelia infection in patients with morphea.19,20
- Morphealike lesions have also been reported to occur after BCG, tetanus, and mumps-measles-rubella vaccinations. Whether the vaccinations themselves or the trauma from the injections was the inciting event is not clear.
- Drug-induced morphea: This is only rarely reported (ie, from bleomycin, D-penicillamine, L-5-hydroxytryptophane, balicatib).21
- Trauma: Some morphea patients report a history of local trauma directly preceding the onset of disease. Excessive physical exertion triggers eosinophilic fasciitis in approximately half the cases.
- Hormones
- Genetics: A few familial cases of morphea have been reported, most commonly the disabling pansclerotic subtype. No significant HLA associations have been described.
More on Morphea |
 Overview: Morphea |
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Further Reading
Clinical trials
Keywords
morphea, morphoea, guttate morphea, keloidal morphea, nodular morphea, bullous morphea, generalized morphea, linear morphea, linear scleroderma, localized scleroderma, plaque-type morphea, atrophoderma of Pasini and Pierini, en coup de sabre, progressive hemifacial atrophy, progressive facial hemiatrophy, Parry-Romberg syndrome, deep morphea, morphea profunda, subcutaneous morphea, eosinophilic fasciitis, Shulman syndrome, disabling pansclerotic morphea
