Morphea

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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]

Although rare, epidemiologic studies suggest 0.9-5.7% of patients with morphea progress to systemic sclerosis.[3] The transition may be marked by the development of Raynaud phenomenon and nailfold capillary changes. However, these patients may have been initially misclassified on diagnosis.

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]

Epidemiology

Frequency

United States

The incidence of morphea has been estimated as approximately 0.4-2.7 per 100,000 people.[12] 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.

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.[13]

Race

Although morphea occurs in persons of all races, it appears to be more common in whites, who comprise 73-82% of patients seen.[12]

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.

History

Morphea is usually asymptomatic, and the development of lesions is typically insidious.

Extracutaneous involvement is present in 20% of patients.[14] Extracutaneous manifestations are more common in the linear and generalized subtypes.

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.

Circumscribed morphea

Circumscribed morphea, also known as morphea en plaque, is the most common subtype of morphea. Patients present with fewer than 3 discrete lesions, predominantly on the trunk. Circumscribed morphea may be divided into superficial and deep variants, with the superficial variant being the most common.

Superficial variant

In the superficial variant, 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. See the image below.


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Inflammatory plaque-type morphea on the abdomen, characterized by induration, erythema, and a surrounding lilac ring.

Patients can present with single or multiple lesions. Oval plaques on the trunk are often oriented with their long axes in a horizontal direction and typically have an asymmetric distribution. Superficial circumscribed morphea is more common on the trunk (especially the lower aspect) than on the extremities, and the face is usually spared. Plaques often develop in areas of pressure, such as the hips, around the waist, and around the bra line in women.

Deep variant

The deep variant of circumscribed morphea (previously referred to as subcutaneous morphea or morphea profunda) primarily involves the subcutaneous fat and underlying structures such as muscle and fascia. 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. The overlying epidermis may be uninvolved, atrophic, or indurated. The lesions are frequently hyperpigmented, but because of the deeper level of inflammation, they lack the other color changes typical of superficial circumscribed morphea. Distribution of lesions is often symmetric. See the image below.


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Deep morphea involving the left lower extremity, with thickened, taut, bound-down skin.

Other variants of circumscribed morphea

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 a superficial 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.

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

Generalized morphea is a more extensive and severe form of plaque-type disease, occurring in 7-9% of morphea patients. Generalized morphea is defined as more than 4 indurated plaques larger than 3 cm each and/or involving 2 of more of 7 anatomic sites (head-neck, each extremity, anterior trunk, and posterior trunk) but sparing the face and hands. 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 trunk/limb, en coup de sabre, and Parry-Romberg variants.


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A hyperpigmented band of linear morphea involving the left 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 75-95% of cases.[15, 16] 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.[17, 18] 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 and may be associated with underlying ocular and central nervous system involvement. Scalp involvement results in scarring alopecia. Loss of eyebrows and eyelashes can also occur in this variant.


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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.

Progressive hemifacial atrophy, also known as Parry-Romberg syndrome, 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, approximately 71% of patients also exhibit cutaneous sclerosis reminiscent of en coup de sabre.[19]

Pansclerotic morphea

Pansclerotic morphea of children is the most debilitating form of morphea. It 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. Significant morbidity, including muscle atrophy, joint contractures, and nonhealing ulcers, is associated.

Mixed

Mixed variant morphea refers to patients who exhibit 2 or more subtypes described above. It occurs in up to 15% of patients with morphea.[4, 16]

General examination

Extensive truncal morphea may lead to restricted respiration.

Complete physical examination is recommended, including genital and oral mucosa. Genital lichen sclerosus has been reported with high frequency in patients with morphea.[20, 21]

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, limb-length discrepancies, and severe muscle 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.[22] Signs of carpal tunnel syndrome may be evident in patients with deep morphea affecting the wrist.

Ocular manifestations are most common in the en coup de sabre variant of morphea and include ptosis, ectropion, extraocular muscle dysfunction, anterior uveitis, episcleritis, glaucoma, xerophthalmia, and keratitis.[23]

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.[4, 24] 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.

Laboratory Studies

Laboratory tests have a limited role in the evaluation of patients with morphea. The following studies can be considered on a case-by-case basis (eg, to monitor disease activity) but generally are not required:

Imaging Studies

Other Tests

Outcome measures currently used in morphea studies include durometer measurements of skin hardness, cutometer measurements of skin elasticity and relaxation, and computerized methods for assessing skin lesions.[41] Clinical skin scoring methods include the modified skin score, based on degree of thickening and percent involvement, as well as the Localized Scleroderma Skin Severity Index (LoSSI), Localized Scleroderma Skin Damage Index (LoSDI), and Physician Global Assessment of Localized Scleroderma disease Damage, which take into account disease activity and damage.[42]

Procedures

Although a presumptive diagnosis of morphea can frequently be made based on clinical findings, a biopsy can be used to confirm the diagnosis and delineate the depth of involvement.

Histologic Findings

The histologic findings of morphea and systemic sclerosis are similar, with a fundamental process of thickening and homogenization of collagen bundles. The depth of involvement is important for categorization into the morphea subtypes. The sclerotic process in superficial circumscribed morphea is centered in the lower reticular dermis, whereas other variants are characterized by replacement of the subcutaneous fat and underlying tissues by collagen. See the image below.


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Histopathology of mature scleroderma; full-thickness sclerosis of the dermis. Photomicrograph courtesy of Dirk Elston, MD.

The epidermis is usually normal, but rete ridges may become flattened later in the disease course.

In the early inflammatory stage, a perivascular and interstitial variably dense infiltrate of lymphocytes admixed with plasma cells and occasional eosinophils is observed in the reticular dermis and/or the fibrous trabeculae of the subcutaneous tissues. Blood vessel walls demonstrate endothelial swelling and edema, and thickening of preexisting collagen bundles and deposition of fine, wavy fibers of newly formed collagen occur.

In the late sclerotic stage, the inflammatory infiltrate typically disappears. Collagen bundles in the reticular dermis and subcutis become thick, closely packed, and hyalinized. Atrophic eccrine glands appear to be trapped within the middle of the thickened dermis as subcutaneous fat is replaced by collagen. A paucity of blood vessels is seen, and adnexal structures are progressively lost. Depending on the subtype, the process of sclerosis may extend into the fascia and even underlying muscle; in contrast, thickened collagen bundles are restricted to the dermis in superficial morphea.

Reports of lichen-sclerosus–like changes (edematous, homogenized collagen) in the papillary dermis have been described in lesions of morphea.[43]

Medical Care

Although several regimens have shown benefit in case series, few controlled trials have been performed. In general, therapy aimed at reducing inflammatory activity in early disease is more successful than attempts to decrease sclerosis in well-established lesions.

Lesions of superficial circumscribed morphea often undergo gradual spontaneous resolution over a 3- to 5-year period. Limited disease can often be managed with topical therapy or lesion-limited phototherapy.

Patients with potentially disabling generalized, linear, or deep morphea typically require more aggressive therapy.

Surgical Care

Consultations

Medication Summary

In general, therapy aimed at reducing inflammatory activity in early disease is more successful than attempts to decrease sclerosis in well-established lesions. The approach to treatment of the various subtypes of morphea is described in Medical Care. Note that phototherapy represents another important modality.

Triamcinolone acetonide (Aristocort, Kenalog)

Clinical Context:  Medium-potency corticosteroid that reduces inflammation and may prevent progression of sclerosis.

Clobetasol propionate 0.05% cream or ointment (Temovate)

Clinical Context:  Superpotent topical corticosteroid that reduces inflammation and may prevent progression of sclerosis.

Prednisone (Deltasone, Orasone)

Clinical Context:  Reduces inflammation and prevents progression of sclerosis. Systemic corticosteroid therapy (often used in combination with MTX; see below) is appropriate for patients with active inflammatory disease that is widespread, severe, and/or potentially disfiguring/disabling.

Class Summary

These agents reduce inflammation and suppress collagen synthesis.

Calcipotriene 0.005% ointment (Dovonex)

Clinical Context:  Synthetic vitamin D-3 analog that can lead to softening of morphea lesions.

Class Summary

These agents inhibit fibroblast activity and TGF-beta production and have anti-inflammatory effects.

Methotrexate (Rheumatrex, Trexall)

Clinical Context:  Antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA and RNA synthesis in lymphocytes and other immune cells. This and other mechanisms lead to an anti-inflammatory effect, which is reflected in reduced levels of circulating cytokines such as IL-2, IL-6, and IL-8 (indicators of disease activity) in morphea patients. Response is often delayed until 1-3 mo after initiation of therapy.

Class Summary

These agents can reduce inflammation associated with morphea.

Tacrolimus 0.1% ointment

Clinical Context:  The mechanism of action of tacrolimus is not known. Reduces itching and inflammation by suppressing the release of cytokines from T cells. Also inhibits transcription for genes that encode IL-3, IL-4, IL-5, GM-CSF, and TNF-alpha, all of which are involved in the early stages of T-cell activation. Additionally, may inhibit release of pre-formed mediators from skin mast cells and basophils, and downregulate expression of FCeRI on Langerhans cells. Can be used in patients as young as 2 years old. Drugs of this class are more expensive than topical corticosteroids. It is available as an ointment in concentrations of 0.03 and 0.1%. Indicated only after other treatment options have failed.

Mycophenolate

Clinical Context:  Inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses denovo purine synthesis by lymphocytes, thereby inhibiting their proliferation. Inhibits antibody production.

Two formulations are available and are not interchangeable. The original formulation, mycophenolate mofetil (MMF, Cellcept) is a prodrug that once hydrolyzed in vivo, releases the active moiety mycophenolic acid. A newer formulation, mycophenolic acid (MPA, Myfortic) is an enteric-coated product that delivers the active moiety.

Complications

Prognosis

Author

Jennifer V Nguyen, MD, Resident Physician, Department of Dermatology, Hospital of the University of Pennsylvania

Disclosure: Nothing to disclose.

Coauthor(s)

Nicole Fett, MD, Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

Victoria P Werth, MD, Professor of Dermatology and Medicine, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, Philadelphia Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Peter Fritsch, MD, Chair, Department of Dermatology and Venereology, University of Innsbruck, Austria

Disclosure: Nothing to disclose.

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Disclosure: Nothing to disclose.

Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas School of Medicine at San Antonio

Disclosure: Nothing to disclose.

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania

Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds Investigator; Genentech Grant/research funds investigator; Centocor Consulting fee Consulting; Abbott Grant/research funds investigator; Abbott Consulting fee Consulting; Novartis investigator; Pfizer Grant/research funds investigator; Celgene Consulting fee DMC Chair; NIAMS and NHLBI Grant/research funds investigator

Chief Editor

Dirk M Elston, MD, Director, Ackerman Academy of Dermatopathology, New York

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Michael Girardi, MD, Kendra G. Bergstrom, MD, and Julie V. Schaffer, MD, to the development and writing of this article.

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Inflammatory plaque-type morphea on the abdomen, characterized by induration, erythema, and a surrounding lilac ring.

Deep morphea involving the left lower extremity, with thickened, taut, bound-down skin.

A hyperpigmented band of linear morphea involving the left part of the trunk and thigh.

Linear atrophic depression of an en coup de sabre lesion on the right side of the forehead and the frontal part of the scalp.

Histopathology of mature scleroderma; full-thickness sclerosis of the dermis. Photomicrograph courtesy of Dirk Elston, MD.

Inflammatory plaque-type morphea on the abdomen, characterized by induration, erythema, and a surrounding lilac ring.

A hyperpigmented band of linear morphea involving the left part of the trunk and thigh.

Linear atrophic depression of an en coup de sabre lesion on the right side of the forehead and the frontal part of the scalp.

Deep morphea involving the left lower extremity, with thickened, taut, bound-down skin.

Histopathology of mature scleroderma; full-thickness sclerosis of the dermis. Photomicrograph courtesy of Dirk Elston, MD.