Morphea 

Updated: Jun 17, 2020
Author: Victoria P Werth, MD; Chief Editor: Dirk M Elston, MD 

Overview

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:

  • Radiation therapy: Morphea can occur at the site of previous radiation therapy for breast cancer and other malignancies, developing from 1 month up to more than 20 years after irradiation.[13, 14] Involvement may extend beyond or distant to the irradiation field.[15]

  • Chimerism: Immature chimeric cells have been found in morphea lesions, suggesting that such nonself cells may lead to an autoimmune phenotype.[16]

  • 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]

  • 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.

  • Drug-induced morphea: This is only rarely reported (ie, from bisoprolol, bleomycin, D-penicillamine, L-5-hydroxytryptophane, balicatib, pembrolizumab, interferon beta-1a, ustekinumab).[15, 23, 24, 25, 26]

  • 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, 27]

  • Genetics: A few familial cases of morphea have been reported, most commonly the disabling pansclerotic subtype. No significant HLA associations have been described.[28, 29]

  • Chemical exposure (link)[30]

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 white individuals, 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, worsening of disease, or a relapsing-remitting course.[31]

Linear lesions tend to persist for longer than plaque-type lesions, but they often improve over the years. However, linear morphea, including 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.

In a prospective cohort study of 130 morphea patients on a treatment plan tailored according to disease severity, disease activity for morphea appeared to improve over 6-12 months, while sclerosis improved more slowly over 2-5 years. Treatments included topical steroids for mild activity, ultraviolet (UV)‒A1 phototherapy for superficial, generalized lesions, or methotrexate with or without corticosteroids for severe activity. UVA1 phototherapy lasted 30-40 treatments, while the duration of methotrexate treatment was up to 2.5 years. However, patients should be monitored long term, as the disease course can wax and wane.[32]

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).[33] 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.[34]

 

Presentation

History

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

Extracutaneous involvement is present in 20% of patients.[16] Extracutaneous manifestations are more common in the linear and generalized subtypes.

Malaise, fatigue, myalgias, and arthralgias are common extracutaneous symptoms. Arthralgias are usually localized to an affected extremity. Linear and deep lesions can also be associated with arthritis, carpal tunnel syndrome, and other peripheral neuropathies.

Dysphagia (esophageal dysmotility or reflux), dyspnea, and vascular complaints also are reported.

Neurologic manifestations, which are more common in patients with en coup de sabre or progressive hemifacial atrophy, include 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.

Dry eyes are also frequently reported due to eyelid or lacrimal gland sclerosis.

Physical Examination

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.

Inflammatory plaque-type morphea on the abdomen, c 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.

Deep morphea involving the left lower extremity, w 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.

A hyperpigmented band of linear morphea involving 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.[35, 36] 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.[37, 38] 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.[39]

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.

Linear atrophic depression of an en coup de sabre 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.[40]

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, 36]

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.[41, 42]

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.[43] 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.[44]

Oral findings in patients with craniofacial morphea include altered dentition, malocclusion, and asymmetry of the tongue.

Complications

In the linear and deep morphea subtypes, joint contractures, subcutaneous atrophy, and growth failure can be deforming and disabling. Rarely, pansclerotic morphea can give rise to chronic ulcers as well as squamous cell carcinoma of the skin.[16]

 

DDx

Diagnostic Considerations

Also consider the following:

  • Linear melorheostosis
  • Linear lupus erythematosus panniculitis
  • Linear atrophoderma of Moulin
  • Lipodermatosclerosis
  • Radiation fibrosis
  • Reflex sympathetic dystrophy
  • Scleromyxedema
  • Cheiroarthropathy due to diabetes mellitus
  • Carcinoid syndrome
  • Muckle-Wells syndrome
  • Stiff skin syndrome
  • Restrictive dermopathy
  • Progeria
  • Sclerodermoid conditions caused by chemical/toxin exposures (ie, polyvinyl chloride, epoxy resins, pesticides, dry cleaning solvents, silica dust)
  • Sclerodermoid conditions caused by iatrogenic agents (ie, bleomycin, taxanes, gemcitabine, uracil-tegafur, melphalan isolated limb perfusion, L-tryptophan, vitamin K injections, pentazocine injections, silicone or paraffin implants)

Some of the entities in the differential diagnosis above often manifest with a sclerodermoid (ie, diffuse sclerosis) rather than morpheaform (ie, discrete areas of sclerosis) morphology.

Atrophoderma of Pasini and Pierini and eosinophilic fasciitis are generally viewed as part of the morphea spectrum.[45] Lichen sclerosus and morphea can coexist, with clinical and histologic findings of both conditions present in the same patient and even within the same lesion.[42, 41] In addition, lichen sclerosus, discrete morpheaform plaques, diffuse sclerodermoid changes, and eosinophilic fasciitis all can occur as manifestations of chronic graft versus host disease.

The differential diagnosis for early, erythematous lesions of plaque-type morphea may include the following:

  • Inflammatory granuloma annulare

  • Interstitial and granulomatous dermatitis

  • Erythema migrans

  • Fixed drug eruption

  • Annular lichenoid dermatitis of youth

  • Sweet syndrome (early)

  • Interstitial mycosis fungoides

  • Port wine stain

Differential Diagnoses

 

Workup

Laboratory Studies

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

CBC count

CBC count results are usually normal. Peripheral eosinophilia is most often present in patients with eosinophilic fasciitis and forms of deep morphea, but it may be observed in those with early, active morphea of any type.

Erythrocyte sedimentation rate

This is usually normal, but it may be elevated in patients with extensive, active morphea.

Autoantibodies

Serum autoantibodies are commonly present in all types of morphea. Their clinical and prognostic significance remains unclear.

Rheumatoid factor is positive in 15-60% of morphea patients, most often children with linear morphea.

Antinuclear antibodies are present in approximately 20-80% of morphea patients, typically with a homogeneous, speckled, or nucleolar pattern. The prevalence is higher in patients with generalized, linear, and deep subtypes.

Anti–single-stranded DNA antibodies are present in 25% of patients with plaque-type morphea, in 75% of those with generalized morphea, and in 50% of those with linear morphea; levels correlate with extensive, active disease and joint contractures.[46]

Antihistone antibodies are present in 47-87% of morphea patients overall and in 85% of those with generalized morphea, correlating with the number of plaque-type lesions and the total area affected.[47] The antihistone antibody titers may be related to the extent of involvement and the disease activity in linear scleroderma.[46]

Anticentromere, anti-Scl70, and anti–double-stranded DNA antibodies are present in less than 5% of morphea patients.[4]

Antibodies to matrix metalloproteinase (MMP)-1 have shown to be significantly elevated in 46% of morphea patients.[48]

Antiphospholipid antibodies are present in some morphea patients. Immunoglobulin M and immunoglobulin G anticardiolipin antibodies are present in 60% and 25% of patients with generalized morphea, respectively. Lupus anticoagulant can also be detected in approximately 50% of this subgroup of patients.

Antitopoisomerase II-alpha antibodies are present in 76% of morphea patients.

Anti-Cu/Zn-superoxide dismutase antibodies are present in 90% of morphea patients.

Imaging Studies

Radiography

Radiography may be helpful in cases of linear (including en coup de sabre) or deep morphea in which involvement of the underlying bone is suspected. It can also be used to monitor pediatric patients for potential growth defects.

Magnetic resonance imaging

MRI of the brain and skull in patients with en coup de sabre and Parry-Romberg syndrome may reveal abnormalities such as cortical atrophy, subcortical calcifications, white matter lesions, ventricular dilatation, leptomeningeal enhancement, anomalous intracranial vasculature, and skull atrophy, even in the absence of neurological symptoms.[44]

MRI is useful for demonstrating the depth of lesions in deep and generalized morphea. Typical findings include diffuse edema of the subcutaneous tissues with thickening, increased signal intensity on T2-weighted images, and contrast enhancement of the fascial planes.

Ultrasonography

The 10- to 25-MHz ultrasound can measure skin thickness, which correlates with disease activity. The 10- to 15-MHz ultrasound is available in the United States. Ultrasonography can be of great benefit in the evaluation and monitoring of localized scleroderma.[49, 50] Color Doppler ultrasound has also been used to assess disease activity.[51]

Laser Doppler flowmetry and infrared thermography

These can be complementary tools to detect active lesions.[16]

Electroencephalography

Abnormalities may be observed in patients with craniofacial linear morphea, usually localized to areas of the brain underlying affected skin, and sometimes without a history of clinical seizure activity.

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.[52] 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.[53]

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.

For superficial circumscribed and generalized morphea, a deep punch biopsy (including subcutaneous fat) is usually sufficient. Different histologic features are seen at the sclerotic center versus the inflammatory border of the lesion, and thus the location of the biopsy should be noted.

For linear and deep morphea, an incisional biopsy extending down to muscle is required to document fascial 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.

Histopathology of mature scleroderma; full-thickne 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.[54]

 

Treatment

Medical Care

Although several regimens have shown benefit in case series, few controlled trials have been performed and data suggest wide variation in the approach to treatment.[55] In general, therapy aimed at reducing inflammatory activity in early disease is more successful than attempts to decrease sclerosis in well-established lesions.[56]

Superficial circumscribed morphea

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.

Treatment of active lesions with superpotent topical or intralesional corticosteroids may help reduce inflammation and prevent progression, although there is a lack of data supporting their efficacy. A typical regimen includes alternating every other day a super-potent topical steroid with a steroid-sparing agent, such as tacrolimus or calcipotriene.

Tacrolimus 0.1% ointment applied twice daily was shown to be effective as monotherapy for limited plaque morphea compared with placebo in a 12-week, small, double-blind, placebo-controlled study.[57, 58]

Topical calcipotriene may also be beneficial, especially when nightly occlusion (eg, with plastic wrap) is used to increase penetration of the medication.[59] The combination of topical calcipotriol with betamethasone dipropionate has also been reported effective.[60]

Imiquimod 5% cream 3-5 times per week has been shown to decrease lesional erythema and induration in small series.[61, 62, 63]

Generalized, linear, or deep morphea

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

Successful treatment of severe and/or rapidly progressive morphea with systemic corticosteroids (eg, high-dose intravenous methylprednisolone in monthly pulses or oral prednisone at various intervals) in combination with weekly low-dose methotrexate (MTX) has been reported in several case series.[64] A randomized, double-blind, placebo-controlled trial demonstrated the efficacy of combination therapy with oral prednisone and methotrexate in children with active morphea.[65] MTX alone can also be effective and has been used successfully as long-term therapy in both adults and children.[66, 67, 68, 69, 70] To minimize the risk of relapse, the recommended treatment duration of MTX is at least 2 years.[71]

Systemic corticosteroids can be helpful in the inflammatory phases of morphea, but they have little benefit for established sclerosis and are not recommended for long-term monotherapy given their risk of adverse effects and tendency for relapse with discontinuation.

Mycophenolate mofetil has been shown to be an alternative agent to methotrexate. It is believed to function through antifibrotic mechanisms.[52, 72, 73] A 2020 multicenter, retrospective cohort study of 77 morphea patients demonstrated 87% of patients had improvement or stable morphea after 9-12 months.[74]

A few reports describe responses of severe morphea to cyclosporine and everolimus.[75, 76, 77]

The use of hydroxychloroquine to treat morphea has been advocated, but little documentation of success is present in the medical literature. However, in 2019, a retrospective study of 84 adults with morphea treated with at least 6 months of hydroxychloroquine showed 43% of patients had a complete response, with only 7.1% having no response.[78]

Despite promising results in case series involving both adults and children, oral calcitriol did not lead to significant improvement in a double-blinded placebo-controlled trial.[79, 80]

Phototherapy can also be considered a first-line therapy for patients with generalized, superficial morphea given its low adverse effect profile compared with immunosuppressive agents.[81] There are many types of phototherapy, including narrowband UVB (310-311 nm), broadband UVB, broadband UVA (320-400 nm), long-wavelength UVA (UVA1; 340-400 nm, low- or medium-dose), and psoralen plus UVA chemotherapy (PUVA). All modalities have been reported to be beneficial, with UVA being the most studied to date. UVA-based phototherapy modalities (broadband UVA, UVA1, PUVA—both oral and bath) have all been shown to improve morphea lesions in multiple case series and a randomized controlled trial.[82]

PUVA (both bath and systemic) was found effective in a sm-ll uncontrolled study and case series.[83, 84] A combination of acitretin and PUVA has also shown efficacy.[85]

UVA1, unlike broadband UVA, consists only of the deeper penetrating UVA wavelengths. In a randomized trial comparing the efficacy of different forms of phototherapy for morphea, medium dose UVA1 (50 J/cm2) was found to be significantly more effective than narrowband UVB. However, there was no difference in clinical efficacy between narrowband UVB and low-dose UVA1 (20 J/cm2) or between medium- and low-dose UVA1. Despite these findings, the use of UVA1 is limited as only some academic centers have UVA1 units.[86]

Narrowband UVB therapy, although less potent owing to its limited dermal penetration, can also be beneficial and is the most commonly used phototherapy modality for patients.[86] Regimens combining UV therapy with topical corticosteroids or calcipotriene may also be superior to either method alone.[86, 87]

Few cases have shown benefit using extracorporeal photopheresis, particularly for generalized deep morphea.[88, 89]

In one case report, treatment of plaque-type morphea with the 585-nm pulsed dye laser led to substantial improvement.[90]

In one case report, treatment of generalized morphea with concomitant mycophenolate and intravenous immunoglobulin (IVIG) showed significant improvement.[91]

Bosentan has shown benefit for refractory cutaneous ulcerations in pansclerotic morphea. It is an endothelin receptor antagonist with vasodilatative and antifibrotic properties.

Other approaches aim to alter the inflammatory milieu but await further study. These include topical halofuginone (transforming growth factor-beta synthesis inhibitor), TNF-alpha inhibitors, imatinib, JAK inhibitors, and thalidomide (interleukin 12 and tumor necrosis factor-alpha inducer).[92, 93, 94]

A randomized, double-blinded, placebo-controlled trial demonstrated no benefit with intralesional interferon gamma.[95]

Abatacept has been reported effective in treating morphea with deep tissue involvement in a small case series.[96]

Tocilizumab has been reported effective in treating juvenile morphea in patients who did not respond to methotrexate/mycophenolate in small case series and reports.[97, 98]

Surgical Care

Orthopedic surgery may be indicated if patients develop deformities of the joints and bones as sequelae of linear or deep morphea. Such surgical interventions include release of joint contractures and limb-lengthening procedures.

Dermatologic and plastic surgeons can help correct deformities due to atrophy of subcutaneous tissues. Reconstruction of the face and scalp may be beneficial to patients with en coup de sabre and Parry-Romberg syndrome, with possible use of tissue expansion and implants of autologous bone, fat, or synthetic materials (eg, polyethylene).[99, 100, 101]

Consultations

Referral to a dermatologist can help establish the diagnosis and initiate appropriate treatment of morphea, as there are demonstrated gaps in care with a wide range of approaches.[102]

Consultation with a physical and occupational therapist and a program of physical therapy are of utmost importance in maintaining range of motion and function of the extremities in patients with linear or deep morphea that crosses joint lines. Programs typically include passive stretching, muscle strengthening, and resting splints.

Ophthalmologic screening is indicated for children with head and neck lesions and/or concomitant central nervous system involvement.[44]

Consultation with a neurologist is helpful for patients with craniofacial morphea who present with neurologic symptoms or have abnormalities detected via MRI of the brain.

Orthopedics and oral and maxillofacial surgery should be consulted as needed for bony and structural abnormalities.[103]

Consultation with a dentist is required when craniofacial morphea leads to altered dentition or malocclusion.

 

Medication

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.

Corticosteroids

Class Summary

These agents reduce inflammation and suppress collagen synthesis.

Triamcinolone topical (Kenalog Orabase, Kenalog topical, Pediaderm TA)

Triamcinolone is a medium-potency corticosteroid that reduces inflammation and may prevent progression of sclerosis.

Clobetasol propionate 0.05% cream or ointment (Temovate)

Clobetasol propionate is a superpotent topical corticosteroid that reduces inflammation and may prevent progression of sclerosis.

Prednisone (Deltasone, Orasone)

Prednisone reduces inflammation and prevents the 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.

Vitamin D analogs

Class Summary

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

Calcipotriene 0.005% ointment (Dovonex)

Calcipotriene is a synthetic vitamin D-3 analog that can lead to softening of morphea lesions.

Antirheumatic agents

Class Summary

These agents can reduce inflammation associated with morphea.

Methotrexate (Rheumatrex, Trexall)

Methotrexate is an 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 months after initiation of therapy.

Immunosuppressant Agent

Tacrolimus ointment (Protopic)

The mechanism of action of tacrolimus is not known. It reduces itching and inflammation by suppressing the release of cytokines from T cells. It 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, it may inhibit release of preformed mediators from skin mast cells and basophils and down-regulate the expression of FCeRI on Langerhans cells. It can be used in patients as young as 2 years. Drugs of this class are more expensive than topical corticosteroids. It is available as an ointment in concentrations of 0.03 and 0.1%. It is indicated only after other treatment options have failed.

Mycophenolate

Mycophenolate inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses denovo purine synthesis by lymphocytes, thereby inhibiting their proliferation. It 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.

 

Questions & Answers

Overview

What is morphea?

What is the pathophysiology of morphea?

What causes morphea?

What is the incidence of morphea in the US?

What are the racial predilections for morphea?

How does the incidence of morphea vary by sex?

Which age groups are at highest risk for morphea?

What is the prognosis of morphea?

What is the mortality and morbidity of morphea?

Presentation

What are the signs and symptoms of morphea?

Which physical findings are characteristic of morphea?

What is circumscribed morphea?

How are the lesions of the superficial variant of circumscribed morphea characterized?

How are the lesions of the deep variant of circumscribed morphea characterized?

How are guttate morphea lesions characterized?

How are Keloidal (nodular) morphea lesions characterized?

How are atrophoderma of Pasini and Pierini lesions characterized?

How are bullous morphea lesions characterized?

How is generalized morphea defined?

What are the clinical presentations of linear morphea variants?

What is pansclerotic morphea?

What is mixed morphea?

What are the physical findings characteristic of morphea?

What are complications of morphea?

DDX

Which conditions should be included in the differential diagnoses of morphea?

Which conditions should be included in the differential diagnoses of early, erythematous lesions of plaque-type morphea?

What are the differential diagnoses for Morphea?

Workup

What is the role of lab tests in the workup of morphea?

Which CBC count results suggest morphea?

Which erythrocyte sedimentation rate suggests morphea?

What is the role of autoantibodies in the evaluation of morphea?

What is the role of radiography in the workup of morphea?

What is the role of MRI in the workup of morphea?

What is the role of ultrasonography in the workup of morphea?

What is the role of laser Doppler flowmetry and infrared thermography in the workup of morphea?

What is the role of electroencephalography in the workup of morphea?

How is skin assessed in the workup of morphea?

What is the role of biopsy in the diagnosis of morphea?

Which histologic findings are characteristic of morphea?

Treatment

Which treatments are most effective for morphea?

What are the treatment options for superficial circumscribed morphea?

What are the treatment options for generalized, linear, or deep morphea?

What is the role of hydroxychloroquine and oral calcitriol in the treatment of morphea?

What is the role of phototherapies in the treatment of morphea?

Which investigational therapies have shown benefit for the treatment of morphea?

What is the role of surgery in the treatment of morphea?

Which specialists should be consulted in the treatment of morphea?

Medications

What is the role of medications in the treatment of morphea?

Which medications in the drug class Immunosuppressant Agent are used in the treatment of Morphea?

Which medications in the drug class Antirheumatic agents are used in the treatment of Morphea?

Which medications in the drug class Vitamin D analogs are used in the treatment of Morphea?

Which medications in the drug class Corticosteroids are used in the treatment of Morphea?