Background

Morphea (localized scleroderma [LS]) is a form of pathologic sclerosis that is typically limited to the skin and underlying structures. In contrast to SSc, there are typically no sclerodactyly or nailfold capillary abnormalities, and morphea is much less frequently associated with Raynaud phenomenon. In general, morphea affects only the skin, although involvement of the subcutaneous fat, fascia, and even muscle and bone can be seen in some variants. In addition, rarely there can be associated central nervous system involvement when it presents on the face and head. Several studies have suggested that morphea can also be associated with arthralgias, ocular involvement (usually as aforementioned central nervous system manifestation), and gastrointestinal symptoms stemming from esophageal dysmotility and reflux.

The pathogenesis of morphea is unclear, but it is characterized by excess collagen deposition caused by both excess production and decreased degradation. The exact initiating events are unclear, although infection, trauma, radiation, or medications have all been implicated. Borrelia organisms have been linked to LS in Europe but not in the United States, and thus their role remains unclear. In morphea skin there is upregulation of various adhesion molecules, as well as release of key cytokines such as transforming growth factor β (TGF-β), as well as platelet-derived growth factor, connective tissue growth factor, and interleukins 4, 6, and 8.

Epidemiology

Morphea is rare, with an estimated incidence ranging between 0.4 and 2.7 per 100,000 people based on very few epidemiologic studies. It most frequently affects whites, but may occur in all races. There is a female predominance at a ratio of 2.4:1 to 4.2:1. Disease prevalence is equally distributed between adults and children; however, plaque-variant morphea comprises most adult cases, whereas linear morphea is the most common variant in children.

Classification and Subtypes

Morphea (or LS) can present in a variety of clinical phenotypes, but there is no uniformly accepted classification scheme. In 1995, Peterson and colleagues proposed a classification scheme that distinguishes plaque, generalized, deep, bullous, and linear types as the 5 main subtypes of LS. This classification scheme has been widely accepted, but has some drawbacks. For instance, it does not take into account that children may present with more than 1 subtype of morphea, or that bullous lesions might appear in all different LS subtypes. In 2006, Laxer and Zulian proposed an alternative classification scheme to overcome these weaknesses, but in 2009 a German group of experts proposed a final classification that considers the depth and extent of fibrosis and refers to the treatment of the respective subtypes ( Table 1 ).

The classic plaque type of morphea is the most frequent subtype, especially in adults. Initially it can present as oval-shaped lesions surrounded by an erythematous border (appears as a “lilac ring”), which then later become sclerotic in the center ( Fig. 1 ). However, some morphea lesions can present purely as pink or hyperpigmented macules and patches that never become indurated. These lesions are often called superficial morphea (see later discussion). Morphea lesions are typically found on the trunk and area between the hip and inguinal regions, although the breasts and extremities are commonly involved. In general, the hands, feet, and head are spared. Guttate morphea is a rare subtype that presents with multiple small sclerotic lesions, yellow or white in color with a shiny surface. These lesions may be confused with extragenital lichen sclerosis clinically and histopathologically ( Fig. 2 ).

Morphea, plaque type. Shown is an indurated oval plaque with a lilac colored border and a yellow, indurated center.

Morphea, guttate and superficial type. Shown is a classic lesion with lichen sclerosus et atrophicus overlap, consisting of atrophic, hypopigmented macules with areas of follicular plugging ( black dots ).

Idiopathic atrophaderma of Pierini and Pasini (IAPP) is a form of dermal atrophy that manifests as single or multiple sharply demarcated, round to oval, hyperpigmented to erythematous, nonindurated depressed papules and plaques. It is relatively poorly described in the literature, but is known to have a predilection for the trunk (particularly the back) and occurs predominantly in young healthy women in their teens and second decade. The patches seen in IAPP are marked by a slight depression of the skin with an abrupt edge (“cliff-drop border”). The precise classification of IAPP has been long debated. Some consider it a variant of LS or morphea, as presented in the German classification (see Table 1 ), but others disagree with this classification because there are certain features to suggest that IAPP and morphea are separate entities. IAPP lacks sclerosis as a feature, and lesions commonly merge over time, creating a moth-eaten appearance (Swiss cheese–like appearance) not consistent with typical morphea. The more recently described term superficial morphea has become a more accepted way to describe IAPP given its lack of sclerosis and its hypopigmented or hyperpigmented appearance ( Fig. 3 ).

Morphea, superficial type. This patient has large truncal hyperpigmented patches on the back without any induration.

Generalized LS is a more severe subtype of LS, as it is characterized by 4 or more indurated plaques greater than 3 cm in diameter involving 2 or more anatomic sites (head and neck, each extremity, anterior trunk, and posterior trunk) according to Laxer and Zulian. These plaques are often symmetric and can coalesce over time.

Disabling pansclerotic morphea is a very rare and severe variant of LS that predominantly occurs in children, leading to rapidly progressive and extensive involvement of skin, subcutaneous fat, fascia, muscle, and even bone. Pansclerotic refers to involvement of all layers of the skin, not necessarily implying total body involvement. It can lead to severe contractures, musculoskeletal atrophy, poorly healing ulcerations, and skin necrosis.

Eosinophilic fasciitis (Shulman syndrome) is another rare form of LS characterized by symmetric, often painful swelling, and induration and thickening of the skin and soft tissue. After some time lesions may become more indurated and fibrotic, leading to a peau d’orange–like appearance. The onset is often abrupt and can be triggered by intense physical activity or mechanical trauma. Clinically, eosinophilic fasciitis exclusively affects the extremities but, in contrast to SSc, typically spares the hands and feet. If only the deep tissues are involved, the overlying skin can feel soft, but deep palpation reveals very firm tissue beneath. A helpful clinical sign is to have the patient raise the arms above the head and to look for longitudinal furrowing, which represents sparing of deep sclerosis in the area of the veins (so-called groove sign). Diagnosis is based on characteristic skin abnormalities, thickened fascia, and perivascular inflammatory infiltrates composed of lymphocytes and/or eosinophils. A peripheral eosinophilia is frequently seen but is not mandatory in making the diagnosis.

Linear LS is the most common LS subtype in children, and is characterized by band-like lesions arranged longitudinally on the extremities. In mild disease the lesions can heal with some hyperpigmentation, but in more severe disease linear LS can lead to flexion contractures, muscle atrophy, severe growth retardation, myositis, and arthritis. The most well-recognized linear subtype is “en coup de sabre,” which affects the frontoparietal region of the head, usually ranging from the eyebrows to the hair-bearing scalp where it can cause scarring alopecia. This subtype can also affect the central nervous system, causing seizures and headache or ophthalmologic findings such as uveitis. Many have suggested that progressive facial hemiatrophy (Parry-Romberg syndrome) and en coup de sabre are actually the same entity. Progressive hemifacial atropy is a rare condition marked by unilateral facial atrophy affecting the skin, subcutaneous tissue, muscles, and potentially even bone. Sometimes skin fibrosis is absent in this subtype, which typically affects children and adolescents. It coincides simultaneously up to 40% of the time with linear LS en coup de sabre.

The deep subtype of LS, deep morphea, is the rarest variant, accounting for fewer than 5% of all cases of LS. In deep morphea, the deeper connective tissue layers including fat, fascia, and muscle tend to be affected by fibrosis. The lesions are typically symmetric and are located on the extremities. This subtype may occur in childhood.

The histology of morphea depends on the clinical subtype, as changes can be seen in the epidermis, dermis, and subcutaneous fat. Early lesions show thickened collagen bundles in the reticular dermis and dense inflammatory infiltrates around blood vessels and adnexa ( Fig. 4 ). Later stages contain tightly packed collagen fibers with absent or atrophic sweat glands, while the subcutaneous fat may be either absent or “trapped” more superficially in the lower reticular dermis.

Morphea, skin biopsy. There is a superficial and deep perivascular inflammatory cell infiltrate with dense, pink dermal collagen and attenuated spaces between collagen bundles (hematoxylin and eosin stain, original magnification ×100).

Trauma

In a large retrospective study examining 750 children with morphea-like lesions, approximately 9% of patients reported some type of mechanical trauma (including insect bites and vaccination) to the affected area before disease onset. In the literature there are 8 cases reported of sclerodermoid reactions after vaccination, and several vaccines are implicated, including the measles/mumps/rubella, hepatitis B, and tetanus vaccines. Different theories for the pathogenesis of these cutaneous reactions have been postulated, including hypersensitivity to the vehicle or preservative in the vaccine as well as trauma from the injection itself. Local sclerodermoid injection-site reactions have also been reported, most commonly with vitamin K, as well as with other less commonly reported injectable agents such as progesterone and vitamin B ₁₂ .

Medications and Chemicals

Several medications have been linked to the development of morphea-like lesions, including bisoprolol, bleomycin, peplomycin, d -penicillamine, bromocriptine, pentazocine, balicatib, and l -5-hydroxytryptophane in combination with carbidopa ( Box 2 ). However, medication-induced lesions mimicking morphea are a rare occurrence, and the literature is derived from case reports. The pathogenesis of these drug-induced reactions is not completely understood, but a profibrotic effect caused by collagen synthesis and fibroblast growth has been described for bleomycin, peplomycin, and dopaminergic drugs. d -Penicillamine has been known to interfere with collagen and elastin maturation and synthesis, and possibly with regulatory T cells. In a recent clinical trial testing the cathepsin K (catK) inhibitor, balicatib, for the treatment of osteoporosis, 9 of 709 treated patients developed morphea-like skin changes, whereas there were no reports of cutaneous reactions in the placebo group. The skin fibrosis in these patients is thought to have been due to the inhibition of matrix-degrading functions of catK in the skin, therefore skin fibrosis may be a class effect of catK inhibitors.

Occupational exposure to various chemical and physical agents has been associated with the development of scleroderma-like cutaneous disorders. The literature on such associations is sparse, with most of the knowledge arising from individual case reports, but historically organic solvents and compounds such as vinyl chloride monomers, benzene, trichloroethylene, toluene, and naphthalene have been associated with the development of SLD. The link between these compounds and SLD has been described in 2 case-control studies.

Many studies also highlight the toxicity of pesticides, and the relationship between exposure to pesticides and the development of cutaneous sclerotic diseases. A recent case series reports development of a scleroderma-like cutaneous sclerosis in children exposed to pesticides containing malathion and diniconazole. Unfortunately, the mechanism of action of these pesticides and others remains unclear.

Radiation

Postirradiation morphea-like reactions are a potential complication after radiation therapy, particularly in cancer treatment. Women receiving radiation for the treatment of breast cancer are particularly at risk, with manifestations in other parts of the body being much rarer. The incidence of postirradiation morphea-like lesions has been reported to be approximately 1 in 500 irradiated patients. Onset of the cutaneous lesion typically occurs within a year of radiation, although latencies of up to 32 years have been described. Radiation-induced morphea-like lesions have to be differentiated from chronic radiodermatitis, bacterial cellulitis, or recurrence of an inflammatory type of cancer. Therefore, a diagnosis of postirradiation morphea must be confirmed by histologic examination whereby an inflammatory and a sclerosing phase can be seen. The inflammatory changes are characterized by superficial and deep perivascular and interstitial lymphoplasmacytic infiltrate, and the sclerosing changes are marked by thickening of collagen bundles in the reticular dermis. Radiation is thought to cause localized sclerodermoid reactions by affecting a clonal fibroblast population, causing selective local immune alteration and altering endothelial cells.

Treatment

Topical therapies for morphea include corticosteroids, calcipotriol, and calcineurin inhibitors such as tacrolimus or pimecrolimus. Systemic corticosteroids tend to be used in linear, generalized, or deep forms of morphea. Methotrexate has the best evidence for efficacy as a disease-modifying agent, alone or in combination with corticosteroids. Mycophenolate mofetil has also been suggested as an effective therapy for methotrexate-resistant disease. Several other systemics have been reported in cases of morphea, including infliximab, bosentan, antimalarial drugs, imatinib, extracorporeal photopheresis, cyclosporine, and penicillin, but their efficacy has yet to be confirmed in large studies. Ultraviolet (UV) light therapy has antifibrotic and anti-inflammatory activity, and case series totaling more than 100 patients have reported effective outcomes primarily for UVA and UVA-1 therapy; UVA (rather than UVB) has been used most often, as UVA penetrates more deeply into the dermis. However, because UV light does not penetrate deeper than the dermis, it is not effective for deeper forms of scleroderma involving the fat, muscle, or bone.