Keywords

Morphea, also called localized scleroderma, is a fibrosing disorder that resembles scleroderma (systemic sclerosis) ­microscopically, but typically has a quite different clinical presentation, course and possible pathophysiology. The individual with morphea has single or multiple circumscribed indurated cutaneous plaques that can have variable appearances, depending on the subtype (see classification below and Table 12.1). The main variants are circumscribed or plaque-type morphea (Fig. 12.1a), generalized morphea (Fig. 12.1b), linear morphea (Figs. 12.1c–f and 12.2a–d), and deep morphea or morphea profunda. Unlike scleroderma, systemic disease and involvement of internal organs are uncommon in morphea.

Table 12.1 Classification of morphea
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Fig. 12.1
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(a) Plaque type morphea : Young adult man with an indurated flesh colored plaque with a faintly erythematous border on the right chest. (b) Generalized morphea: 9-year-old girl with numerous sclerotic pink and ivory colored plaques on the trunk. (c, d) En Coup De Sabre (linear morphea of the face) : 15-year-old girl with several year history of progressive linear depressions on her forehead (d). The appearance of the early inflammatory plaque without significant sclerosis in (c) demonstrates how morphea can be misdiagnosed as a vascular lesion. (d) shows the sclerosis after 4 years. (e, f) Parry-Romberg Syndrome (linear morphea of the face) : 4-year-old girl with progressive linear depressions on her lower face (f) involving the chin, mandible, neck and tongue (e)

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Fig. 12.2
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(a) Linear morphea of the extremity : 12-year-old girl with sclerosis, dyspigmentation and asymmetric growth of the right lower extremity after onset of linear morphea many years ago. (b–d) Linear morphea of the extremity associated with disabling contractures : Several examples of contractures on foot and hands in children with longstanding linear morphea

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The classic appearance of the most common forms of morphea is indurated or sclerotic dyspigmented (i.e. hyper or hypopigmented) plaques sometimes with a violaceous border. The development of morphea can be insidious and subtle. Initial misdiagnosis as other skin disorders, particularly by non-dermatologists, occurs. Early morphea can mimic other quite different cutaneous diseases. These include, among others, atrophic conditions such as lichen sclerosis, vascular lesions such as port wine stains (Fig. 12.1c), depigmenting disorders such as vitiligo [1], and even more common skin lesions such as bruises and scars. Because of this variable presentation, diagnosis and treatment of early morphea can be delayed or inappropriate [1–3]. Skin biopsy is often helpful in differentiating morphea from these other disorders.

There are several excellent recent reviews of morphea covering a large number of case reports and small case studies [4–15]. This review will concentrate on the English language literature for morphea from the 2000s to the present.

Practical guidelines for assessment and management of morphea are presented at the end of this chapter.

Classification of Morphea

The subtypes include plaque-type morphea, generalized morphea, linear morphea, morphea profunda, pansclerotic disabling morphea (which may be a subtype of morphea profunda) and mixed types of morphea. Clinical images of the morphea subtypes are presented in Fig. 12.1. The classification scheme was developed by the Committee on Classification Criteria for Juvenile Systemic Sclerosis, composed of members of the Pediatric Rheumatology European society (PRES), the American College of Rheumatology (ACR), and the European League Against Rheumatism (ELAR) [8] (Table 12.1). Diagnosis is mainly by clinical features, as the histopathology is similar in all the forms except eosinophilic fasciitis and atrophoderma of Pasini and Pierini (Fig. 12.3a). Some believe that these last two disorders are separate entities.

Fig. 12.3
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(a) Atrophoderma of Pasini and Pierini : Preadolescent girl with several year history of a large plaque and small patches of atrophy on the lumbar back. The lesions have a sharp drop-off with a “punched out” appearance and are not indurated clinically. (b) Pansclerotic disabling morphea : Rapid onset of diffuse sclerosis and hyperpigmentation of the hands and arms resulted in contractures of the fingers reminiscent of systemic scleroderma in this 13-year-old girl

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When linear morphea occurs on the upper face most notably the paramedian forehead, it is often called en coup de sabre (ECDS)(Fig. 12.1c, d). When it involves the lower face or produces hemifacial atrophy of deeper tissues, it is often called Parry-Romberg syndrome (Fig. 12.1e, f). Whether these conditions are a spectrum of the same disorder or are two distinct entities has been a subject of considerable debate, but recent literature suggests that they are on the same spectrum of disease [16].

Epidemiology of Morphea

Morphea is diagnosed more often in whites and females than in individuals of color or in males. The disorder occurs predominantly in young individuals and children with an incidence of 0.4–1 per 100,000 individuals or 25 cases per 1 million individuals [13, 17–24]. There is a female: male ratio of 2–3.1 [19, 21]. Morphea is approximately 0.2% of the patients referred to a general pediatric dermatology clinic [21]. In general, guttate or plaque-type morphea is more common in adults, and linear morphea is more common in children, with the highest incidence in young white girls.

Clinical features of morphea. The clinical appearance of morphea is a puzzle itself – plaques of indurated skin are found immediately adjacent to normal skin without induration. Genetic factors surely play a role in the clinical appearance of morphea, particularly the linear variants which often follow Blaschko’s lines [7, 25]. Blaschko’s lines are different from dermatomal skin patterns and are thought to represent embryonic pathways of skin cell development. They reflect genetic mosaicism that is invisible in the normal individual and apparent in some of the genodermatoses such as epidermal nevus, incontinentia pigmenti and Goltz syndrome, and in acquired skin disorders such as linear lichen planus and lichen striatus. Cutaneous mosaicism can involve mutations in either keratinocytes (epidermal nevus, incontinentia pigmenti) and/or fibroblasts (focal dermal hypoplasia or Goltz syndrome). In linear morphea, presumably the fibroblasts in the affected area have a different genetic footprint than adjacent normal skin. The mutations are not known, but extensive molecular evaluation of scleroderma fibroblast genes may ultimately provide clues to similar genetic alterations in affected skin in morphea.

Clinical course of morphea. Disease activity of morphea, particularly plaque type, can resolve in 3–5 years, but reactivation may occur [21]. The course is variable depending on the subtype. Linear morphea tends to be more chronic. Overall, the course is benign, with survival no different from the general population [13]. There is significant morbidity associated with the linear forms however, including joint contractures, limb length and size discrepancy, arthritis/arthralgias, and neurologic/ophthalmologic consequences when morphea occurs on the scalp and face (see Morbidity below). Other symptoms include dysphagia and dyspnea [13]. The main complaints for the most common form, plaque-type morphea, are skin tightness, itching, and unfavorable cosmetic appearance.

Morbidity in morphea. Quality of life assessments show that individuals with morphea have better outcomes than those with disabling severe atopic dermatitis, with the exception of the more severe forms of morphea affecting face and limbs [26].

A variety of morbidities are reported more frequently in the linear [27] and generalized or mixed subtypes [11] of morphea. The more commonly associated complications include musculoskeletal and deep soft tissue abnormalities, neurologic/ophthalmologic problems, and other extracutaneous complications including gastrointestinal, vascular, pulmonary, renal and cardiac problems. Malignancy is a rare associated morbidity. Few systematic studies have been performed because of the rare frequency of morphea and even more rare co-existing morbidities [23].

  • Musculoskeletal and soft tissue complications. The most common extracutaneous finding in morphea patients is arthritis/arthralgias, which has been reported in 12% of pediatric patients with morphea [27]. Both articular and soft tissue/bony abnormalities are typically associated with linear morphea. Other musculoskeletal complications include joint swelling, myalgia, and limb contractures [8, 11] (Figs. 12.2b–d and 12.3b). Spontaneous fractures [28], unexplained muscle atrophy [29], hemiatrophy [30] and osteomyelitis [31] have also been reported. Morphea can be preceded by unexplained skin edema [32, 33] or atrophy [29]. One case of linear morphea presented as a neuromuscular disorder with muscle atrophy, weakness and loss of arm function [34]. Individuals with facial linear morphea can have dental abnormalities [35] and even ipsilateral tongue hypoplasia (Fig. 12.1e).

  • Neurologic complications. Neurologic involvement was reported in 4% of pediatric patients with morphea [27]. It is more common in patients with linear morphea of the face. Complications include seizures, headache, and peripheral neuropathy among others. Intractable partial seizures [36], epileptic encephalopathy [37], and status migrainicus [38] have all been reported in association with morphea. Epilepsy can precede the development of en coup de sabre [39, 40]. Localized epilepsy, often refractory to medications, is the most common complication of linear morphea of the face [41]. Kistger et al. reviewed 54 patients with craniofacial scleroderma who also had neuroimaging (head CT or MRI) for neurological symptoms. They found some common atypical features on imaging including atrophy, calcifications and T2 hyperintensities. Others have described abnormal MRI results in patients with Parry–Romberg syndrome [42].

  • Ophthalmologic complications. Ocular involvement was reported in 2% of pediatric patients with morphea [27]. Ocular involvement in morphea is also more common in patients with linear morphea that affects the face although it has also been reported to occur in patients without facial skin lesions [43]. Associated ophthalmologic abnormalities may include anterior uveitis, episcleritis, glaucoma, xerophthalmia, keratitis and, strabismus.

  • Other extracutaneous complications. Gastrointestinal involvement, namely esophageal motor function abnormalities causing acid reflux and/or dysphagia, has been reported in approximately 2% of pediatric morphea patients [27]. Vascular complications including Raynaud’s phenomenon are also reported in about 2% of patients [27]. Pulmonary involvement can present with dyspnea and is rare. Renal complications include nephritis [27], unilateral renal artery stenosis and immunoglobulin M nephropathy [44]. Cardiac complications include pericarditis and arrhythmias due to supraventricular ectopic beats and runs [45]. These systemic complications of morphea indicate that disease is not just “skin deep.”

  • Malignancy. Rare cases of malignancy are reported in morphea lesions, such as squamous cell carcinoma of the lip that developed in an individual with pansclerotic disabling morphea [35]. The etiology is likely similar to carcinoma developing in chronic venous insufficiency ulcerations and burn scars.

Autoimmunity in morphea. Individuals with the variants other than plaque-type morphea can have peripheral eosinophilia and abnormal serologies – the most common are positive antinuclear (ANA) and/or rheumatoid factor, and presence of anti-ssDNA and antihistone antibodies – which suggest autoimmune disease, but do not reliably correlate with disease activity [21, 46, 47]. There are no laboratory tests that confirm the diagnosis of morphea, which is made on clinical and histopathologic criteria. Like other autoimmune diseases such as scleroderma, the autoantibodies are not directly pathogenic, and are likely epiphenomena reflecting immune dysfunction.

The presence of a positive ANA and serum autoantibodies was studied in a cohort of 72 adult and pediatric patients with linear morphea [48]. The authors found no differences in ANA-positivity or type of autoantibody between children and adults. Antihistone and anti-dsDNA antibodies tended to be associated with more severe disease in children. Autoantibody titers do not appear to correlate with disease activity but can reflect the burden of disease.

In another study, positive autoantibodies occurred in individuals with morphea with an incidence of 46–80% (ANA), 50% (anti-ssDNA), 47% (anti-histone antibodies),and 26% (rheumatoid factor) [49]. Sato [50] reported that 46% of individuals with morphea have anti-cardiolipin antibodies and 24% have positive lupus anticoagulant tests. Approximately 16% of patients in a small study (n  =  41) had increased serum antibodies to matrix metalloprotease-1 by ELISA [51]. Elevated serum B-cell activity factor (BAFF) in individuals with morphea is higher compared with normal controls, particular in generalized morphea [52].

Positive ANA and body surface area of involvement had prognostic value in a retrospective study of 35 adults and children with plaque-type (n  =  15), generalized [15], linear morphea [4] and eosinophilic fasciitis. The majority of patients on treatment improved clinically and by morphometric measurements of skin induration (53%). Failure to improve or stabilize after a mean follow-up of 29 months was associated with generalized morphea and/or positive ANA [53].

An interesting but unexplained feature of autoantibodies found in morphea patients is that they are mainly those of lupus, not scleroderma, which morphea resembles clinically and microscopically. Rare cases of morphea with scleroderma autoantibodies such as anti-centromere antibodies are described [54].

In a larger study of 245 individuals with morphea that included 123 adults and 122 children, there was a high prevalence of concomitant autoimmune disease (18%) and familial autoimmune disease (16%). These authors found a strong association between the generalized and mixed morphea subtypes and markers of a “systemic autoimmune process” which included high frequency of concomitant autoimmune disease, extracutaneous complications, and abnormal serologies (i.e. ANA). They suggested that patients with these subtypes of morphea (generalized and mixed) should be monitored closely for the presence of systemic and autoimmune disorders and treated with immunosuppressive therapy when appropriate [11].

Similarities and differences between morphea and scleroderma. Scleroderma (systemic sclerosis) occurs mainly in adult women and is characterized by not only skin sclerosis, but also visceral sclerosis (lungs, kidneys, and esophagus). The presentation of scleroderma is different from morphea. Scleroderma typically begins in acral skin and progresses proximally, often involving the trunk. Patchy involvement as seen in morphea is uncommon. Extensive cutaneous and visceral disease in scleroderma has significant morbidity and increased mortality.

Molecular genetic studies in morphea. Milano et al. [55] used gene array analysis to establish a genetic “fingerprints” for scleroderma subsets, including morphea, compared with normal controls. They identified 5 significantly different gene expression change clusters: diffuse-proliferation, inflammatory, limited, and normal-like. Gene expression profiles from 3 biopsies of morphea skin fell into the inflammatory category which was characterized by markers for increase in immune response, response to pathogen, humoral defense, lymphocyte proliferation, chemokine binding, chemokine receptor activity, and response to virus. The gene array results overall confirm and further refine the distinct subsets of scleroderma, and demonstrate that morphea can potentially be differentiated from those subsets at a molecular level.

Overlap autoimmune disorders and other skin disorders in morphea. The role of genetics in autoimmune diseases is important yet incompletely understood, particularly in morphea. There are no specific mutations that are associated with morphea but familial morphea and morphea in association with other autoimmune disorders occurs, suggesting a genetic predisposition [11, 46, 56, 57]. Some clues to an “autoimmune phenotype” – a genetic predisposition to autoimmune disease – are seen in these familial and overlap forms of connective tissue disease. For instance, of 47,361 individuals with rheumatoid arthritis in a Swedish study, there was a significant risk (SIR2.4) of morphea in their offspring [58]. Morphea can also coexist rarely with other autoimmune diseases, most often reported as case studies. These unusual overlap disorders include morphea variants with other connective tissue and autoimmune diseases such as scleroderma [59], systemic lupus erythematosus [60, 61], rheumatoid arthritis [58], inflammatory bowel disease [62], autoimmune thyroid disease [63, 64], vitiligo [63, 65, 66], alopecia areata, Type I diabetes mellitus [62], antiphospholipid syndrome [67], necrotizing vasculitis [68], as well as mixed types of morphea [16, 69, 70]. Other types of inflammatory skin disorders can also be associated rarely with morphea such as psoriasis [71], lichen planopilaris [72], lichen sclerosis [73], and lichen striatus [74]. A case of morphea in association with Rosai-Dorfman disease is reported [75].

Histopathology of morphea. Classic morphea can have a different histopathology depending on the stage of development. The histopathologic changes have been divided into indeterminate (early), inflammatory, mixed inflammatory and sclerotic, and sclerotic (late) stage morphea [76]. As expected by definition, increased T-cells are present in the inflammatory stage compared with normal skin.

  • Like scleroderma, the inflammatory stage of morphea is characterized by dermal edema, and by lymphocytic and histiocytic inflammatory cell infiltrates with plasma cells.

  • The later sclerotic stage is characterized by thickened acellular homogenized-appearing collagen bundles at all levels of dermis, typically seen first in the deep reticular dermis near interface of dermis and fat. The adnexal structures (hair, eccrine glands) are surrounded by dense fibrosis with loss of fat around the eccrine glands in chronic disease (Fig. 12.4a–e).

    Fig. 12.4
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    (a) Skin biopsies of morphea have a characteristic “squared off” shape because of the dense dermal sclerosis. There are patchy perivascular mononuclear cell infiltrates of lymphocytes, histiocytes and occasional plasma cells, but otherwise the dermis is acellular compared with normal skin. Flattening and atrophy of the epidermis is associated with underlying sclerosis. Hair follicles and sebaceous glands normally seen in a skin biopsy of hair-bearing skin are absent. (Magnification  =  2.5×). (b) This specimen shows the characteristic “bottom up” sclerosis that can be seen in morphea before entire dermis is involved. The sclerotic collagen is in the lower half of dermis, while normal collagen is in the upper half. Dense collagen has replaced normal collagen from the arrow down. The left upper corner of the image also shows the edge of an atrophic hair follicle. (Magnification  =  5×). (c, d) Higher power views of the non-sclerotic (c) and sclerotic (d) dermal areas show that the collagen in the sclerotic area has lost the fine fibrillar texture of normal collagen seen in non-sclerotic areas (Magnification  =  40×). (e) Encasement of adnexal structures by dense collagen with loss of the fat around eccrine glands is shown. Eventually, atrophy of hair follicles, sebaceous glands, and eccrine glands (arrow) occurs in long-standing morphea. (Magnification  =  20×)

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  • The atrophic stage is characterized by dermal atrophy and eventual disappearance of adnexal structures.

Eosinophilic fasciitis is considered by some to be a deep version of morphea with the fibrotic changes in the deep dermis and fascia, which are thickened and contain hypertrophied collagen bundles. There is typically a dense perivascular inflammatory cell infiltrate composed of lymphocytes, histiocytes, plasma cells and eosinophils in the fascia.

A clinical and pathologic study of 17 patients with atrophoderma of Pasini and Pierini showed similar histopathology in all cases, some of which were compared with unaffected skin in the same individual [77]. There was no atrophy, sclerosis, or entrapment of adnexal structures. The only abnormal finding in elastic tissue stained sections was reduced total numbers of elastic fibers, many of which were fragmented.

Elastic fibers in the skin in morphea. [76, 78] Morphea can resemble a scar microscopically; elastic fiber staining with elastic van Gieson histochemistry can be helpful in distinguishing the two entities because elastic fibers are lost in scars but not in morphea. Walters [78] describes preservation of elastic fibers in all biopsies of morphea by histochemistry (n  =  28). There were straightened compressed fibers with parallel orientation between sclerotic collagen bundles in both scleroderma and morphea which are indistinguishable microscopically.

Therefore, histochemistry and immunohistochemistry (see below) are helpful in distinguishing morphea from other ­clinical mimics such as scars, hemangiomas, and vitiligo.

Immunohistochemical studies of morphea. Investigators have evaluated matrix molecules, dendritic cells and immune cells in morphea by immunohistochemistry. Not all of these studies used uninvolved skin of the same individual for comparison unfortunately.

CD34 and Factor XIIIa (FXIIIa) in normal skin. CD34 and Factor XIIIa (FXIIIa) immunostaining identifies two different populations of dermal dendritic cells. Both are found in embryonic mesenchyme and persist in adult tissue. CD34 (hematopoietic progenitor cell antigen) is a membrane marker for many types of cells including hematopoietic stem cells, endothelial cells, embryonic fibroblasts, and fibrocytes [79, 80]. In normal skin, there are numerous dendritic CD34+ cells with fine processes scattered among collagen bundles of reticular dermis in a diffuse pattern. These cells are likely fibrocytes, a normal component of skin that function in wound repair [80]. FXIIIa  +  cells include platelets, megakaryocytes, bone marrow cells, tissue monocyte/macrophages, and dermal dendrocytes, which are found mainly in papillary but not reticular dermis in normal skin. FXIIIa is a protransglutaminase component of the coagulation cascade that is activated by thrombin and calcium to cross-link fibrin in clot formation (“fibrin stabilizing factor”). It also functions to cross-link matrix proteins, including collagen.

CD34+ and FXIIIa  +  cells in the skin in morphea. In scleroderma and morphea, the immunostaining pattern is reversed when compared with normal skin. CD34 immunostaining is lost and FXIIIa is gained in the areas of sclerosis [1, 76, 81–83]. When fibrocytes become activated, they become CD34-negative smooth muscle actin–positive myofibroblasts and secrete collagen. It is a plausible hypothesis that FXIIIa  +  tissue macrophages appear in active areas of sclerosis and cross-link the new collagen synthesized by the now CD34-negative fibrocytes [1].

UVA1 phototherapy for morphea may act by changing the cytokine and stromal microenvironment to favor persistence and not loss of the CD34 dermal dendritic cells and return to normal collagen synthesis and degradation [84]. In one study in which CD34 and FXIIIa immunostaining was evaluated after UVA1 phototherapy, the UVA1 was less effective in restoring CD34+ dermal dendrocytes in linear (n  =  2) than in plaque type morphea (n  =  5). UVA1 also decreases inhibitory Smad7 expression in morphea, another possible effect on fibrosis [85].

T-cells and antigen-presenting cells in the skin in morphea. Immunostaining for various immune markers on biopsy specimens from morphea patients shows increased numbers of T-cells (CD3+, CD4+, CD8+) and dendritic cells (CD1a+, CD25+, CD57+) compared with normal controls (p  <  0.05). CD30+ cells were approximately the same in that study [86]. The finding is not surprising — no effort was made to compare with other similar skin diseases such as scar and comparable inflammatory disorders, or with uninvolved skin from the same individual to establish specificity of the findings for morphea.

Macrophages in the skin in morphea. CD68, CD163 (hemoglobin scavenger receptor), and CD204 (Class A scavenger receptor molecule) have high expression on alternatively activated M2 macrophages in morphea [87]. M2 macrophages are important in the early stages of fibrosis—they have an IL-10 low, IL-23 low, IL10-high phenotype and influence wound repair and sclerosis by releasing TGF-beta. Similar increases in activated macrophages have been reported in systemic sclerosis [87].

Melanocytes in the skin in morphea. Sung et al. demonstrated with immunoperoxidase and immunohistochemical staining that there were reduced numbers of melanocytes in the epidermis in 2/3 cases of hypopigmented morphea and 2/4 cases of non-hypopigmented morphea compared with 7 matched biopsies of normal skin [1]. The data suggest a complex immunophenotype in children with morphea that involves more than dermal changes. These data help to explain the hypopigmentation often seen in morphea clinically (approximately 54%) in a set of 35 children with morphea in a pediatric dermatology clinic at UCSF [1].

Cytokines and growth factors in the skin in morphea. Most of the in vivo and in vitro work on fibrosis has been done in scleroderma and in cell cultures of scleroderma fibroblasts. Some information is published on morphea from which we can extrapolate a hypothesis for pathophysiology. There are serum and tissue cytokine alterations similar to scleroderma which are associated with morphea that suggest a mechanism for initiation and perpetuation of the fibrotic phenotype. Immunostaining on skin biopsies of the inflammatory phase of morphea shows increased transforming growth factor (TGF)-beta [88] and insulin-like growth factor, a mediator of extracellular matrix homeostasis [89]. Increased circulating TGF-beta1, intercellular adhesion molecule −1 (ICAM-1), interleukin-2 (IL-2) IL-4 and IL-6 in patients with morphea may promote increased collagen synthesis and fibroblast proliferation [90–92]. These profibrotic Th2 cytokines along with TGF-beta, PDGF, CTGF and metalloprotease-3 promote the stromal changes of morphea. The immune mediator pathways are complex and not completely worked out. Cytokine therapy has been proposed and tested in a few clinical trials for morphea but as in scleroderma, obtaining appropriate controls and demonstrating efficacy is difficult in a disease which can resolve on its own.

Morphea induced by environmental triggers (Table 12.2). The emergence of morphea following exposure to environmental exposures is intriguing and may provide clues for the pathophysiology of morphea. The triggers fall into the categories of radiation, drugs, trauma, and infection.

Table 12.2 Morphea induced by environmental agents
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Radiation- and surgery-induced morphea [93–100]. Morphea at the site of supervoltage therapy for breast carcinoma is well-described, occurring in approximately 0.2% of women treated for breast cancer from a few months to up to 20 years after the radiation therapy [101]. Another name for the disorder is “radiation port scleroderma”. The association with tamoxifen therapy in the cases involving the breast is questionable; the controlled studies and statistical analysis have not been done. Cases of recurrent radiation-induced morphea after a second surgery but no radiation and following cosmetic surgery alone suggest that the surgery itself may play a role in this variant of morphea [97, 102, 103].

Other rare variants of radiation-induced morphea include

  • Extensive morphea on lower abdomen and upper extremities in a 74-year-old woman with extensive morphea after radiotherapy to the pelvis for endometrial carcinoma [98].

  • Morphea following fluoroscopy [104]

Post-radiation morphea can mimic radiation dermatitis, infection and recurrent breast carcinoma. Differentiating morphea from radiation dermatitis depends on both clinical and histopathological features [93].

  • Radiation injury has dose-related acute erythema and scaling, possibly desquamation, and deep fibrosis in subcutaneous fat, fascia, and muscle that are confined to the radiation port. Bizarre atypical fibroblasts, hyperpigmentation, dermal atrophy, and telangiectasia are microscopic clues to radiation dermatitis, not morphea.

  • Post-radiation morphea has later onset, erythema and induration that are not dose-related. There is rapidly progressive predominantly dermal fibrosis that extends beyond the radiation port.

The pathophysiology of post-radiation morphea is thought to be neoantigen production by ionizing radiation that triggers the pro-fibrotic inflammatory cascade [93]. Tamoxifen may induce TGF-beta production and induce fibrosis, but the pathways are complex and not completely understood.

Drug-induced morphea. Drug-induced morphea is rare, and has been reported for a diverse group of medications from anti-epileptics to chemotherapeutic agents (Table 12.2). In these case reports, the proof of concept was the partial or complete resolution of morphea after stopping the medication [105]. Profibrotic agents associated with drug-induced morphea are bleomycin, peplomycin, dopaminergic drugs and beta-blocking agents [105]. Several agents (i.e. pentazocine) can cause direct vascular injury and dermal sclerosis, likely the etiology for the injection site type of morphea.

Other common themes include interference with signaling pathways [anti-tumor necrosis factor (TNF) alpha agents and balicatab]. Interferons have been used for therapy of morphea with paradoxical results. Intralesional interferon-gamma was reported to be successful for linear morphea in case reports [106] and interferon-gamma was used successfully for ocular symptoms of en coup de sabre [107], presumably because interferon inhibits fibroblast growth and collagen synthesis in vitro. However, the systemic in vivo effects can be quite different from local effects. Interferon-beta therapy for multiple sclerosis may be a trigger for development of morphea in a subset of individuals, suggesting a genetic predisposition to fibrosing disease [108]. Interferon-alpha therapy for myeloproliferative disorders or chronic hepatitis in several case reports resulted in worsening or new onset of scleroderma and morphea, rather than improvement [109–111]. These findings emphasize the complex immunological networks in morphea and scleroderma. It is not always possible to translate in vitro experiments to in vivo therapy with biologic agents which can have many different functions in vivo.

Trauma. In a study of 26 patients with severe juvenile localized scleroderma, four (15% ) reported a history of trauma to the area and one had a history of dental extraction ipsilateral to the area in which morphea developed [23]. Another possible trigger is vibration, thought to be a factor in a case report of a marble cutter who held an electric tool in his left hand and developed extensive sharply demarcated unilateral morphea on the ipsilateral side [112]. He had no lung disease to suggest silica-induced scleroderma. Other instances of fibrosing disease, i.e. sclerodactyly, due to vibration in chainsaw users, metal workers, forestry workers, miners, quarry drillers and stone-carvers have been reported. There are many examples in the literature of injection site morphea, including onset of morphea at the site of vaccinations as well as at the site of an insulin pump placement (observed by these authors) (Table 12.2).

Infection. Borrelia infection is a confounding factor in European studies of morphea because a small percentage (7%) of individuals with morphea has positive Borrelia titers [53]. It is not clear if Borrelia plays a role in pathophysiology of morphea or if this is a coincidental finding because Borrelia exposure is common in Europe [113–116]. Acrodermatitis chronicus atrophicans is thought to be an atrophic variant of morphea induced by Borrelia infection [117].

Pathophysiology of morphea. The reason for the heterogeneity of the morphea variants is a fascinating puzzle yet to be solved. Also fascinating are the rare forms of morphea typically in adults associated with various environmental triggers such as radiation, drugs, trauma, and injected substances, among others (Table 12.2). The variety of disease forms and possible etiologies in morphea suggests that there are many different pathways to skin fibrosis. Hypotheses include autoimmune activation, vascular alterations and injury, and abnormal collagen metabolism. The pathophysiology of infection-induced morphea such as hepatitis and Borrelia infection may be due to activation of hyperaggressive T-cells in response to infection, release of interferons, and by molecular mimicry [115]. There are no hard data for these hypotheses however.

Because of its uncommon incidence predominantly in children and generally benign course, basic laboratory investigation into the pathophysiology of morphea has lagged behind that for scleroderma. We assume that because morphea resembles scleroderma microscopically, it has the same underlying pathophysiology – i.e. alterations in TGF-beta, platelet derived growth factor (PDGF) and other cytokine and growth factor microenvironments, and alterations in pathways of matrix production and collagen metabolism. A combination of these changes could lead to excessive production of normal collagen. As in scleroderma, triggers for disease may include endothelial cell injury and activation of an inflammatory mediator cascade [118]. The experimental data to support these hypotheses for morphea are not available to date, however, and there is no animal model for morphea.

Practical Guidelines for Assessment and Management of Morphea, Overview

Clinical evaluation, although problematic, is still the gold standard for morphea diagnosis and assessment. The classic “active” lesion is a well-circumscribed indurated plaque with a violaceous border, which indicates ongoing inflammation. Disease activity can also be associated with increased warmth of skin lesions as well as increasing size of the plaque/s. Mean time to diagnosis was 1.2 years in a retrospective study of 136 children with morphea [21]. The delay was mainly due to lack of recognition of morphea by primary care physicians. Morphea can rarely present with fever, arthralgias, and lymphadenopathy before the development of obvious sclerosis.

Management of morphea can be challenging because reliable and widely accepted measures for monitoring disease activity in morphea are not available. Clinical evaluation and laboratory testing are not reliable methods for detecting and following disease activity in morphea. Making decisions about choice of initial therapies, intervening with more aggressive therapy, and monitoring effectiveness of therapy are problematic. Development of therapeutic clinical trials and outcome studies depends on objective and validated measures to monitor disease activity, a challenge in the study of morphea.

Assessment of morphea [48, 119, 120]. Unlike scleroderma, where a combination of accepted clinical indices based on skin thickening and sclerotic changes are used to score disease severity [121], scoring severity of disease in morphea with patchy localized cutaneous involvement is more challenging. Many physicians use parameters such as degree of warmth and relative “softness” of the skin to monitor disease course. These methods are subjective however, and quantifiable methods are preferable. The following non-invasive methods do not expose the patient to the risk of poor healing, scarring and the potential for wound infection after skin biopsy; they allow quantifiable and sequential assessment.

Quantifiable Clinical Assessment

  • Skin scores. A modified skin score (MSS) has been used for morphea, but the MSS is only reliable for extensive skin lesions and is not designed to detect subtle increases in size of skin lesions [122, 123]. Another clinical tool to assess morbidity in morphea, the Localized Scleroderma Skin Damage Index, involves calculation of scores for three parameters of cutaneous damage: dermal atrophy, subcutaneous atrophy and dyspigmentation measured at 19 anatomic sites [120]. These scores correlate well with the Physician Assessment of Global Disease Damage, a more general tool for disease in general. However, the scoring system is not applicable to isolated localized lesions.

  • Dermoscopy shows accentuated fibrotic tracts crossed by spreading telangiectasia centrally with an obvious erythematous border peripherally in plaque type morphea [2, 124]. Like dermoscopy of pigmented cutaneous lesions, dermoscopy requires a level of experience with the dermatoscope.

  • Skin thickness can be measured and followed over time using a durometer [123].

  • A computerized method for measuring and following of circumscribed lesions of morphea over time consists of delineating the morphea plaque with transparent adhesive film, transferring to cardboard, and calculating the area of the plaque with specific software [125]. This method includes body surface area (BSA) in its calculations of rate of change over time. Although promising, this method for monitoring disease activity has not yet been evaluated prospectively and is not widely available.

Imaging Methods

  • Ultrasound [126–129]. The most reliable assessment uses 20–25 MHz ultrasound (US). Ultrasound at 10–15 MHz – which is more readily available in the Unites States – is also useful [126, 127]. This modality appears more helpful in making the diagnosis of morphea, rather than for monitoring disease activity [126]. However, ultrasound assessment is operator-dependent and lacks standardization.

  • Magnetic resonance imaging (MRI )[130]. Although the MRI findings in morphea can overlap with other soft tissue abnormalities such as fibromatoses and myofibromatoses, there are some pathognomic features of morphea which distinguish it from those entities. MRI allows evaluation of depth of infiltration and sequential analysis of disease activity.

  • Infrared thermography for detection of disease activity via blood flow changes in early morphea is also an exciting new area of investigation [131]. Infrared thermography uses an infrared camera and Thermosoft software. It is comparable with clinical assessment unless severe atrophy of skin and fat has occurred [23, 131, 132]. In these locations, there are relatively high false positive rates for clinically inactive lesions, especially those located on the face and scalp. This is attributed to increased skin heat conduction because of the relatively thinner skin and decreased density of subcutaneous fat in these areas. Therefore, thermography is less appealing as a reliable tool for monitoring disease activity not only because it appears to be useful only in certain clinical contexts but also because it is not widely available. The combination of infrared thermography and laser Doppler flowmetry – which measures the cutaneous microcirculation – is more effective in these cases [7, 128, 133].

  • All of these methods have not been prospectively evaluated to date, and most are not widely available.

Therapy

Treatment of morphea. Morphea is difficult to treat ---and well-controlled clinical trials are difficult to carry out because of the low incidence of morphea, the lack of objective measures for monitoring disease activity, and the tendency for morphea to regress spontaneously. In children with morphea, clinicians are reluctant to treat aggressively with immune modulators. Because of the morbidities in morphea (see above), early treatment is recommended, particularly of the inflammatory stage of disease [134]. The goal is to limit damage and prevent the sequelae of cutaneous fibrosis.

There are several different strategies for therapy that are based on hypotheses of triggers for morphea:

  • Altering the inflammatory immune cascade: topical corticosteroids, topical calcineurin inhibitors, imiquimod, vitamin D analogues (calcitriol and calcipotriol), methotrexate, mycophenolate mofetil and UVA1 phototherapy all alter the cytokine and growth factor microenvironment of skin. The new biologics also function to change the cutaneous immune environment.

  • Altering the vascular microenvironment: bosetan, an endothelin receptor antagonist, likely functions by altering vascular resistance.

  • Altering the extracellular matrix homeostasis: d-penicillamine inhibits cross-linking of collagen.

The most common topical and systemic therapies reported during the 1980s and 1990s are listed in Table 12.3 [15, 47, 129, 135–139].

Table 12.3 Therapies for morphea
Full size table
Table 12.4 Newer therapeutic agents for morphea – case reports and small clinical trials
Full size table

Topical therapy. [139] (Table 12.3) The mainstay of morphea treatment is topical corticosteroids and more recently, topical vitamin D analogues, calcineurin inhibitors and imiquimod.

Phototherapy. Phototherapy has been a great advance in morphea therapy because it is tolerated well and does not put the patient at risk for the potential side effects associated with systemic treatment with oral immunomodulators [140]. Penetration of the skin by ultraviolet light depends on the wavelength. UVB is not as effective as UVA because it penetrates through only epidermis and superficial dermis. Long wavelength UVA (UVA-1) is not absorbed as effectively by melanin, and the longer wavelength allows the deepest penetration of skin. Thus UVA-1 phototherapy has been used successfully for deep morphea and eosinophilic fasciitis [141, 142]. Other forms of phototherapy used for morphea include topical psoralen with ultraviolet light (PUVA), narrow band ultraviolet B (NbUVB) therapy, and photodynamic therapy which uses light in the visible range [143, 144]. Changes in the cytokine and growth factor microenvironment, induction of metalloproteases, and apoptosis of lymphocytes may all help to explain the beneficial effects of phototherapy in morphea. Side effects of phototherapy include erythema, sunburn, cutaneous photodamage, increased risk of skin cancer and premature ageing. The psoralens can cause gastrointestinal discomfort when taken orally.

The number of treatments per week varies from three to five treatments per week for 20–40 treatments. Although UVA1 is the preferred wavelength, it is not widely available, especially in the US. Therefore, most physicians rely on NbUVB therapy in lieu of UVA1. Encouraging results were reported by Kreuter et al. [145], who demonstrated that although UVA1 was significantly more effective in softening skin lesions of localized scleroderma, NbUVB produced remarkable improvement in skin lesions as well.

Systemic Therapy. The most commonly used systemic therapies include corticosteroids, methotrexate, d-penicillamine, oral calcitriol, and hydroxychloroquine. Guidelines of care for morphea describe these modalities [146, 147]. In general, treatment with the systemic agents is based on type of morphea, extent and location of disease, and likelihood of complications such as disfigurement or functional disability without treatment [9, 15, 136, 148].

An algorithm for therapy of the various types of morphea acute and chronic is presented below.

Initial therapy. First line therapy for morphea is most often topical corticosteroids. For non-facial, well-localized, plaque-type skin lesions, observation is appropriate with the possible addition of super-potent topical steroids and/or topical calcipotriene, which has been demonstrated to soften skin lesions, especially when used under occlusion [149]. Other treatment modalities include physical therapy techniques both for improving range of motion of affected limbs as well as stretching exercises for contractures [21].

Many other agents have been reported as successful in isolated case reports or small open label trials, but none have proved to be uniformly efficacious in double-blind placebo-controlled trials if tested.

Intermediate level treatment for morphea recalcitrant to first line therapies usually includes the use of oral minocycline, hydroxychloroquine, and/or phototherapy. Oral minocycline is not often used in the US to treat morphea but has been used in Europe to treat Borrelia-associated disease [150]. Most dermatologists rely on phototherapy with ultraviolet light as the “next step” beyond topical therapy for more widespread, rapidly spreading, or potentially disfiguring disease.

Aggressive treatment of morphea usually includes the use of D-penicillamine, oral calcitriol, and/or methotrexate in combination with corticosteroids, which is now becoming the treatment of choice for patients with severe disease that threatens function or disfigurement [84, 139, 151–153].

There are other experimental therapies for severe disease which have been tried in a few patients and in small clinical trials. Data from long term follow-up and controlled studies of large numbers of patients are not available to date (Table 12.4).

  • Extracorporeal photochemotherapy and plasmapheresis have been reported in case studies [154, 155].

  • Anti-thymocyte globulin was effective in an individual with rapidly progressive pansclerotic morphea and accompanying pancytopenia due to bone marrow aplasia. The treatment of marrow failure with anti-thymocyte globulin was thought to reverse the abnormal immune process [156].

  • Mycophenolate mofetil is being used more commonly in routine practice to treat morphea patients. Success was reported in arresting disease activity with minimal side effects in a group of pediatric patients who failed methotrexate and corticosteroids [157].

  • Imatinib, a tyrosine kinase inhibitor which interferes with TGF-beta and platelet derived growth factor signaling pathways, has also been reported as successful for one adult patient with therapy-resistant morphea [158].

Surgical Therapies

Linear morphea can be extremely disfiguring, and often fails medical treatment. In certain cases, surgical excision and repair can be considered once the disease activity has “burned out”. Reconstructive surgery with tissue expansion, grafting and scalp reduction of en coup de sabre has been used for disfiguring disease [159]. Autologous fat and artificial bone grafts are also used with some success [160–162]. Autologous fat transplantation using donor sites from the buttocks or abdomen was studied in a series of 20 individuals with stable linear morphea of the face (en coup de sabre). The authors found the procedure more useful for atrophic scarring of morphea over the forehead than over the nose, cheeks or chin where fat survival was less [161]. Successful arthrodesis and flap surgery were described in a case of severe linear morphea over an extremity [163]. Other modalities include use of cosmetic fillers such as Alloderm [164], BoneSource [165], poly-l-Lactic acid and polyethylene implants in facial asymmetry [166, 167].

Summary

In summary, morphea or localized scleroderma is a complex cutaneous disorder with multiple heterogeneous subtypes. There is no reduced mortality, but significant morbidity occurs mainly in the linear forms. Morphea is considered to be an autoimmune disorder because of the presence of autoantibodies; it can be associated with other autoimmune disorders and rarely is familial. The pathophysiology is unknown. The triggers may be similar to scleroderma (vascular injury, abnormal immune regulation, extracellular matrix dysregulation) in genetically susceptible individuals. There are additional clues to pathophysiology in the variants of morphea induced by triggers in the environment such as radiation, trauma, ingestion of certain drugs, injection of foreign materials and infection. Like scleroderma therapy, therapy of morphea is difficult to evaluate because disease tends to resolve spontaneously. The workhorses of therapy include topical corticosteroids, phototherapy, and methotrexate +/−systemic corticosteroids. There are some new immunomodulatory biologic agents for morphea also being tested in small clinical trials.