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 circumscribed, generalized, linear, and pansclerotic subtypes according to the clinical presentation and depth of tissue involvement. [1] Unlike systemic sclerosis, morphea lacks features such as sclerodactyly, Raynaud phenomenon, nailfold capillary changes, telangiectasias, and progressive internal organ involvement. Morphea can present with extracutaneous manifestations, including fever, lymphadenopathy, arthralgias, fatigue, central nervous system involvement, as well as laboratory abnormalities, including eosinophilia, polyclonal hypergammaglobulinemia, and positive antinuclear antibodies. [2, 3, 4]
Pathophysiology
Overproduction of collagen, particularly types I and III 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 autoimmune thyroiditis. [2, 4]
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. TGF-beta also decreases production of proteases, inhibiting collagen breakdown. [5]
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. [6, 7, 8, 9] Other proposed pathophysiologic mechanisms in morphea include the formation of antimatrix metalloproteinase antibodies, as well as increased expression of insulinlike growth factor, which enhances collagen production. [10, 11]
Etiology
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. [4, 12] Patients with generalized morphea are more likely to have a concomitant autoimmune disease, positive serology for autoantibodies, particularly antinuclear antibody, and systemic symptoms. [4] 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. Note the following causes and associations:
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Chimerism: Immature chimeric cells have been found in morphea lesions, suggesting that such nonself cells may lead to an autoimmune phenotype. [16]
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Infection: 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 immunohistochemistry [17] ; however, to date, this has not been demonstrated in patients from the United States. [18, 19] Antibodies to B burgdorferi and high antinuclear antibody titers have been described in patients with morphea, [12] and it has been suggested that Borrelia -associated early-onset morphea may represent a subset of patients with infection-induced autoimmunity. However, results have been conflicting, as other studies have not found a definitive association between Borrelia infection and morphea based on serologic or polymerase chain reaction data. [20, 21, 22]
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Vaccination: Morphealike lesions have also been reported to occur following vaccinations, including BCG, tetanus, and mumps-measles-rubella vaccinations. Whether the vaccinations themselves or the trauma from the injections was the inciting event is not clear.
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Trauma: Some morphea patients report a history of local trauma directly preceding the onset of disease. Plaques of circumscribed morphea often develop in areas of pressure. Reports of morphea lesions following vitamin B-12 and vitamin K injections suggests that trauma from injections may play a role. [15]
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Hormones
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Genetics: A few familial cases of morphea have been reported, most commonly the disabling pansclerotic subtype. No significant HLA associations have been described.
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Chemical exposure (link) [24]
Epidemiology
US frequency
The incidence of morphea has been estimated as approximately 0.4-2.7 cases per 100,000 people. [15] The actual incidence is likely higher because many cases may not come to medical attention. Two thirds of adults with morphea present with plaque/superficial circumscribed 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/superficial circumscribed (25%) and generalized (5%) subtypes. Of note, as many as half the patients with linear morphea have coexistent plaque-type lesions.
Race
Although morphea occurs in persons of all races, it appears to be more common in whites, who comprise 73-82% of patients seen. [15]
Sex
Women are affected approximately three 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.
Prognosis
Superficial circumscribed morphea is a self-limited condition that tends to slowly involute with time; the duration of disease activity of each individual lesion averages 3-5 years; however, patients tend to develop new lesions over their lifetimes.
Initial presentation with generalized morphea and/or positive baseline ANA is associated with a poorer prognosis and worsening of disease. [25]
Linear lesions tend to persist for longer than plaque-type lesions, but they often improve over the years. However, linear morphea, especially the en coup de sabre subtype, may remit and reactivate, remain unchanged, or become more extensive with time. Linear morphea also has a higher rate of relapse compared with other variants. In addition, patients with linear lesions may develop limb atrophy and contractures that result in limited movement and permanent disability. Neurologic and ocular sequelae represent other potential complications of craniofacial linear morphea. Long-term follow-up and serial imaging may be indicated.
Pansclerotic morphea of children is a rare, aggressive, and mutilating variant of deep morphea that begins before age 14 years and has a disease course of relentless progression and severe disability.
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). [26] 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. [27]
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Inflammatory plaque-type morphea on the abdomen, characterized by induration, erythema, and a surrounding lilac ring.
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A hyperpigmented band of linear morphea involving the left part of the trunk and thigh.
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Linear atrophic depression of an en coup de sabre lesion on the right side of the forehead and the frontal part of the scalp.
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Deep morphea involving the left lower extremity, with thickened, taut, bound-down skin.
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Histopathology of mature scleroderma; full-thickness sclerosis of the dermis. Photomicrograph courtesy of Dirk Elston, MD.
