**2. Localized scleroderma, morphea**

### **2.1 Introduction**

Localized scleroderma is a clinically distinct inflammatory disease, primarily of the dermis and also subcutaneous fat [1]. The inflammation leads to scar-like sclerosis. Inflammatory infiltrates and changes of small vessels are similar in morphea and systemic sclerosis (SSc), but morphea has more asymmetric or linear skin localization and distribution than SSc, which has symmetrical distribution. Generalized morphea can prevent and mimic diffuse cutaneous SSc, but this clinical variant does not have Raynaud's phenomenon, digital sclerosis and lung, and

gastrointestinal tract manifestation of the disease. Morphea is responsible for the morbidity of the patient such as skin tightness, joint mobility reduction leading to contractures, growth retardation, and pain [1–3].

### **2.2 Epidemiology**

Morphea typically develops in adults, although morphea can occur at any age. The incidence of morphea is 3 per 100,000 people, and the prevalence of morphea increases with age. The mean age of disease onset is 45 years. Morphea is more prevalent in women than in men (2.6:1), except linear morphea, which has no gender preference [2–4].

### **2.3 Pathogenesis**

The cause of the disease is unknown. Coexistence of various forms of scleroderma and the rare possibility of progression of localized scleroderma into SSc indicate that both types represent different manifestations of the same pathological process. Pathogenesis may be due to participation of environmental influences, immunological disorders, and infections, e.g., association with *Borrelia burgdorferi* [3]. Sclerosis of the skin is induced by vascular damage, activated T cells, and accented connective tissue production by dermal fibroblasts. Vascular changes represent a reduction in the number of capillaries. Enhanced production of collagen and other extracellular matrix proteins and components is induced by T-cell-derived cytokines, interleukin 4 (IL-4), IL-13, and transforming growth factor beta (TGF-β) [3, 5, 6].

### **2.4 Clinical features**

Morphea can be divided into several clinical groups: plaque-type morphea, linear morphea, generalized morphea, deep morphea, nodular morphea, and guttate morphea. Patient with morphea does not have involvement of internal organs and Raynaud's phenomenon. Some patients may have involvement of muscles, tendons, and joints or neurological or ophthalmological symptoms which depend more likely on anatomical site, e.g., in a patient with linear morphea [2].

### **2.5 Plaque-type morphea, circumscribed morphea**

Plaque-type morphea is the most common variant, characterized by a slightly elevated, edematous, erythematous, or violaceous and livid plaque with oval to round or centrifugal distribution (**Figure 1**). The developmental stage of the disease may influence the clinical features: (i) inflammatory, (ii) sclerotic, and (iii) atrophic [1, 2].

### **Figure 1.**

*Plaque-type morphea, lesion on the right side of the trunk. Plaques are surrounded by a dark red rim on the periphery with a yellowish white color center of the lesion as a result of the increasing deposition of connective tissue.*

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**Figure 3.**

*parts with visible scarring.*

*Systemic Sclerosis Mimics*

**Figure 2.**

*DOI: http://dx.doi.org/10.5772/intechopen.88546*

to get rigid and may be slightly painful [2, 3].

*Guttate morphea, multiple nummular lesions on the right thigh.*

dermis and subcutaneous fat (**Figure 3**).

as multiple rather superficial and nummular plaques (**Figure 2**).

In the inflammatory phase, these are delimited striated skin plaques with the accentuated surface by skin pores, which resemble "orange peel" due to the edema of the corium expanding the follicular orifice. Plaques are surrounded by a violaceous rim on the periphery, indicating the active inflammatory stage of the disease. A yellowish-white color develops in the center of the lesion as a result of the increasing deposit of connective tissue [3]. In the sclerotic phase, the inflammatory border is absent. The skin of the lesion is smooth, shiny, and difficult or unable to be shaken. In the final (atrophic) phase, induration disappears; the plaques are soft, slightly sloping for skin and subcutaneous atrophy, and mostly gray-brown pigmented. Circumscribed morphea usually presents as single or multiple skin lesions. It is generally asymptomatic, but the central portion of the progressing lesion starts

A different manifestation of morphea can be present. Guttate morphea presents

Deep morphea represents sclerosis that affects the primarily deep parts of the

*Deep morphea, the affection of the front of the right thigh, mapping distribution of erythematous and whitish* 

*New Insights into Systemic Sclerosis*

**2.2 Epidemiology**

gender preference [2–4].

**2.3 Pathogenesis**

**2.4 Clinical features**

contractures, growth retardation, and pain [1–3].

gastrointestinal tract manifestation of the disease. Morphea is responsible for the morbidity of the patient such as skin tightness, joint mobility reduction leading to

Morphea typically develops in adults, although morphea can occur at any age. The incidence of morphea is 3 per 100,000 people, and the prevalence of morphea increases with age. The mean age of disease onset is 45 years. Morphea is more prevalent in women than in men (2.6:1), except linear morphea, which has no

The cause of the disease is unknown. Coexistence of various forms of scleroderma

Morphea can be divided into several clinical groups: plaque-type morphea, linear morphea, generalized morphea, deep morphea, nodular morphea, and guttate morphea. Patient with morphea does not have involvement of internal organs and Raynaud's phenomenon. Some patients may have involvement of muscles, tendons, and joints or neurological or ophthalmological symptoms which depend more likely

Plaque-type morphea is the most common variant, characterized by a slightly elevated, edematous, erythematous, or violaceous and livid plaque with oval to round or centrifugal distribution (**Figure 1**). The developmental stage of the disease may influence the clinical features: (i) inflammatory, (ii) sclerotic, and (iii) atrophic [1, 2].

*Plaque-type morphea, lesion on the right side of the trunk. Plaques are surrounded by a dark red rim on the periphery with a yellowish white color center of the lesion as a result of the increasing deposition of connective tissue.*

and the rare possibility of progression of localized scleroderma into SSc indicate that both types represent different manifestations of the same pathological process. Pathogenesis may be due to participation of environmental influences, immunological disorders, and infections, e.g., association with *Borrelia burgdorferi* [3]. Sclerosis of the skin is induced by vascular damage, activated T cells, and accented connective tissue production by dermal fibroblasts. Vascular changes represent a reduction in the number of capillaries. Enhanced production of collagen and other extracellular matrix proteins and components is induced by T-cell-derived cytokines, interleukin 4

(IL-4), IL-13, and transforming growth factor beta (TGF-β) [3, 5, 6].

on anatomical site, e.g., in a patient with linear morphea [2].

**2.5 Plaque-type morphea, circumscribed morphea**

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**Figure 1.**

**Figure 2.** *Guttate morphea, multiple nummular lesions on the right thigh.*

In the inflammatory phase, these are delimited striated skin plaques with the accentuated surface by skin pores, which resemble "orange peel" due to the edema of the corium expanding the follicular orifice. Plaques are surrounded by a violaceous rim on the periphery, indicating the active inflammatory stage of the disease. A yellowish-white color develops in the center of the lesion as a result of the increasing deposit of connective tissue [3]. In the sclerotic phase, the inflammatory border is absent. The skin of the lesion is smooth, shiny, and difficult or unable to be shaken. In the final (atrophic) phase, induration disappears; the plaques are soft, slightly sloping for skin and subcutaneous atrophy, and mostly gray-brown pigmented. Circumscribed morphea usually presents as single or multiple skin lesions. It is generally asymptomatic, but the central portion of the progressing lesion starts to get rigid and may be slightly painful [2, 3].

A different manifestation of morphea can be present. Guttate morphea presents as multiple rather superficial and nummular plaques (**Figure 2**).

Deep morphea represents sclerosis that affects the primarily deep parts of the dermis and subcutaneous fat (**Figure 3**).

### **Figure 3.**

*Deep morphea, the affection of the front of the right thigh, mapping distribution of erythematous and whitish parts with visible scarring.*

### **2.6 Linear morphea**

Linear morphea is similar in the clinical feature to circumscribed morphea but with a linear distribution. Linear morphea initially starts as a linear erythematous streak or harmless lesion that later forms a scar-like band (**Figure 4**).

This scar-like band significantly impairs the mobility of the affected limb. Linear morphea can affect the underlying fascia, the muscle, and tendons. Linear morphea that transcends joints can significantly reduce movement and lead to developmental limb defects in children. Rarely, it can form bizarre configurations when copying Blaschko's lines [1, 3, 7].

### **2.7 "En coup de sabre"**

The "en coup de sabre" represents a linear type of morphea of the head. This morphea is unilateral and extends from the forehead into the frontal scalp (**Figure 5**).

It usually starts as a small plaque with the surrounding inflammatory erythematous rim. Parry-Romberg syndrome is a rare variant of linear morphea of the forehead and scalp, with progressive loss of subcutaneous fat, with a smaller share of sclerosis [3, 8, 9].

**Figure 4.** *Linear morphea, linear distribution of plaques, leading to atrophic changes in the affected limb.*

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*Systemic Sclerosis Mimics*

**2.8 Generalized morphea**

*rim spreading to the scalp.*

**Figure 5.**

swallowing difficulties.

**2.9 Laboratory findings**

and rheumatoid factor [1, 13].

**2.10 Histopathology**

different anatomic sites (**Figure 6**).

Generalized morphea begins as multiple plaque-type morphea on the trunk. This clinical variant is defined by the presence of ≥4 plaques involving at least two

*"En coup de sabre" as linear morphea of the head. Linear scarring lesion on the forehead with an erythematous* 

In contrast to systemic sclerosis, generalized morphea does not present with sclerosis primarily involving acral skin or sclerodactyly, but this anatomical site can also be affected [10]. Apart from the skin, generalized morphea can also affect the subcutis and fascia, and be accompanied by slight changes in internal organs (especially the gastrointestinal tract and lungs) and the formation of joint contractures with mostly secondary joint involvement and movement limitation [11, 12]. Carapace-like tightening of the chest, can reduce breathing and cause

Laboratory abnormalities are typically associated with generalized and linear morphea, but some patients with morphea have elevated antinuclear antibody (ANA). Reported rates of ANA positivity among patients with morphea range from 18 to 68%. Other autoantibodies that are detected less frequently than ANA in patients with morphea include anti-single-stranded DNA (ssDNA), anti-doublestranded DNA (dsDNA), antihistone, anti-topoisomerase IIα, antiphospholipid,

The histopathological findings depend on the stage of the disease and area where

T

the biopsy was taken (inflammatory border or central sclerotic lesion). Biopsy

Biopsies performed from inflammatory lesions demonstrate an interstitial and perivascular inflammatory cell infiltrate composed primarily of CD4<sup>+</sup>

specimens for histology must include subcutaneous fat (**Figure 7**).

*DOI: http://dx.doi.org/10.5772/intechopen.88546*

### **Figure 5.**

*New Insights into Systemic Sclerosis*

when copying Blaschko's lines [1, 3, 7].

Linear morphea is similar in the clinical feature to circumscribed morphea but with a linear distribution. Linear morphea initially starts as a linear erythematous

The "en coup de sabre" represents a linear type of morphea of the head. This morphea is unilateral and extends from the forehead into the frontal scalp (**Figure 5**). It usually starts as a small plaque with the surrounding inflammatory erythematous rim. Parry-Romberg syndrome is a rare variant of linear morphea of the forehead and scalp, with progressive loss of subcutaneous fat, with a smaller share of sclerosis [3, 8, 9].

This scar-like band significantly impairs the mobility of the affected limb. Linear morphea can affect the underlying fascia, the muscle, and tendons. Linear morphea that transcends joints can significantly reduce movement and lead to developmental limb defects in children. Rarely, it can form bizarre configurations

streak or harmless lesion that later forms a scar-like band (**Figure 4**).

*Linear morphea, linear distribution of plaques, leading to atrophic changes in the affected limb.*

**2.6 Linear morphea**

**2.7 "En coup de sabre"**

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**Figure 4.**

*"En coup de sabre" as linear morphea of the head. Linear scarring lesion on the forehead with an erythematous rim spreading to the scalp.*

### **2.8 Generalized morphea**

Generalized morphea begins as multiple plaque-type morphea on the trunk. This clinical variant is defined by the presence of ≥4 plaques involving at least two different anatomic sites (**Figure 6**).

In contrast to systemic sclerosis, generalized morphea does not present with sclerosis primarily involving acral skin or sclerodactyly, but this anatomical site can also be affected [10]. Apart from the skin, generalized morphea can also affect the subcutis and fascia, and be accompanied by slight changes in internal organs (especially the gastrointestinal tract and lungs) and the formation of joint contractures with mostly secondary joint involvement and movement limitation [11, 12]. Carapace-like tightening of the chest, can reduce breathing and cause swallowing difficulties.

### **2.9 Laboratory findings**

Laboratory abnormalities are typically associated with generalized and linear morphea, but some patients with morphea have elevated antinuclear antibody (ANA). Reported rates of ANA positivity among patients with morphea range from 18 to 68%. Other autoantibodies that are detected less frequently than ANA in patients with morphea include anti-single-stranded DNA (ssDNA), anti-doublestranded DNA (dsDNA), antihistone, anti-topoisomerase IIα, antiphospholipid, and rheumatoid factor [1, 13].

### **2.10 Histopathology**

The histopathological findings depend on the stage of the disease and area where the biopsy was taken (inflammatory border or central sclerotic lesion). Biopsy specimens for histology must include subcutaneous fat (**Figure 7**).

Biopsies performed from inflammatory lesions demonstrate an interstitial and perivascular inflammatory cell infiltrate composed primarily of CD4<sup>+</sup> T

*Generalized morphea begins as multiple-plaque-type morphea on the abdomen, circularly affecting breasts and the neck. In the margins, lesions are with a rim of erythema, indicating the inflammatory stage of the disease.*

**Figure 7.**

*Deep skin biopsy to subcutaneous fat after formaldehyde fixation.*

cells, eosinophils, plasma cells, and mast cells. Inflammation may extend into the subcutaneous tissues. Furthermore, tissue edema, enlarged tortuous vessels, and thickened collagen bundles may be observed. Biopsy from a sclerotic lesion

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changes [14].

**Figure 8.**

**2.12 Treatment**

**2.11 Differential diagnosis**

*bundles extending into the reticular dermis.*

atrophicans) must be excluded [1, 13, 14].

the spreading of the disease [1, 15].

*Systemic Sclerosis Mimics*

*DOI: http://dx.doi.org/10.5772/intechopen.88546*

demonstrates homogenization of the papillary dermis and thickened collagen bundles extending into the reticular dermis or beyond (**Figure 8**). In biopsy from deep morphea, the deep reticular dermis, subcutis, and fascia show sclerotic

*Biopsy from a sclerotic lesion demonstrates homogenization of the papillary dermis and thickened collagen* 

A number of other disorders can present with clinical features that resemble morphea. Generalized morphea is necessary to distinguish from systemic sclerosis or scleredema diabeticorum. In addition to the skin sclerosis, systemic sclerosis generally begins with the Raynaud's phenomenon, and patients commonly exhibit initial puffiness and eventual sclerosis in the fingertips (sclerodactyly), usually accompanied by nail fold capillary changes. These changes are absent in patients with morphea. The differential diagnosis of plaque-type morphea includes lichen sclerosus, morpheaform basal cell carcinoma, and postirradiation morphea. Furthermore, we need to think of lipodermatosclerosis as fibrosing panniculitis with typical localization on the lower extremities or eosinophilic fasciitis. In some cases of limb involvement, pretibial myxedema or Lyme disease (acrodermatitis

A variety of treatment options are available for patients with active lesions of morphea; however, evidence in support and success of these therapeutics modalities is limited. The expected outcome of successful therapy for morphea is not a complete healing or normal skin texture. In patients with progressive disease, successful treatment presents stopping the formation of new lesions and limiting

**Figure 8.**

*New Insights into Systemic Sclerosis*

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**Figure 7.**

**Figure 6.**

*Deep skin biopsy to subcutaneous fat after formaldehyde fixation.*

cells, eosinophils, plasma cells, and mast cells. Inflammation may extend into the subcutaneous tissues. Furthermore, tissue edema, enlarged tortuous vessels, and thickened collagen bundles may be observed. Biopsy from a sclerotic lesion

*Generalized morphea begins as multiple-plaque-type morphea on the abdomen, circularly affecting breasts and the neck. In the margins, lesions are with a rim of erythema, indicating the inflammatory stage of the disease.*

*Biopsy from a sclerotic lesion demonstrates homogenization of the papillary dermis and thickened collagen bundles extending into the reticular dermis.*

demonstrates homogenization of the papillary dermis and thickened collagen bundles extending into the reticular dermis or beyond (**Figure 8**). In biopsy from deep morphea, the deep reticular dermis, subcutis, and fascia show sclerotic changes [14].

### **2.11 Differential diagnosis**

A number of other disorders can present with clinical features that resemble morphea. Generalized morphea is necessary to distinguish from systemic sclerosis or scleredema diabeticorum. In addition to the skin sclerosis, systemic sclerosis generally begins with the Raynaud's phenomenon, and patients commonly exhibit initial puffiness and eventual sclerosis in the fingertips (sclerodactyly), usually accompanied by nail fold capillary changes. These changes are absent in patients with morphea. The differential diagnosis of plaque-type morphea includes lichen sclerosus, morpheaform basal cell carcinoma, and postirradiation morphea. Furthermore, we need to think of lipodermatosclerosis as fibrosing panniculitis with typical localization on the lower extremities or eosinophilic fasciitis. In some cases of limb involvement, pretibial myxedema or Lyme disease (acrodermatitis atrophicans) must be excluded [1, 13, 14].

### **2.12 Treatment**

A variety of treatment options are available for patients with active lesions of morphea; however, evidence in support and success of these therapeutics modalities is limited. The expected outcome of successful therapy for morphea is not a complete healing or normal skin texture. In patients with progressive disease, successful treatment presents stopping the formation of new lesions and limiting the spreading of the disease [1, 15].

### **2.13 Topical and intralesional treatment**

Topical therapies are unlikely to be effective for the disease involving the subcutis or deeper tissues and are not useful for preventing the development of new lesions in patients with rapidly progressive disease. Topical tacrolimus as tacrolimus 0.1% ointment may be effective for active, inflammatory morphea [16]. High potency topical and intralesional corticosteroids are widely used for the treatment of morphea; however, no formal studies have documented their efficacy. Topical vitamin D—vitamin D as topical calcipotriene 0.005% ointment—may inhibit effects on fibroblast proliferation, collagen synthesis, and T-cell activation. In some clinical studies, an improvement on this therapy was noted in limited numbers of patients [15, 17].

Imiquimod is a topical immunomodulator that induces interferon-gamma, a cytokine that inhibits TGF-beta and the production of extracellular matrix proteins. Imiquimod also downregulates the profibrotic cytokine IL-4. Limited data suggest that imiquimod is effective in some patients with plaque-type morphea [18].

It is possible to use phototherapy in patients with sclerotic diseases like morphea. Longer wavelengths of light as ultraviolet A (UVA) (320–400 nm) are capable of greater depth of penetration into the skin, and most studies of UV phototherapy in sclerotic skin disease have focused on the use of UVA light (320–400 nm). Fewer data are available on the use of PUVA therapy (a combination of UVA and topical or oral use of psoralens) and ultraviolet B (UVB) light (290–320 nm). Phototherapy is unlikely to be effective for morphea with deep involvement (subcutis, fascia, or muscle) and should not be considered as primary therapy alone [19].

### **2.14 Systemic treatment**

Patients with the progressive disease require systemic therapy with methotrexate or corticosteroids. Methotrexate is the most appropriate systemic therapy for morphea. In patients with acute generalized or rapidly progressive disease, we combine treatment with systemic corticosteroids. Methotrexate is typically given for at least 6–12 months with a weekly dose of 15–25 mg. The systemic corticosteroids are usually tapered and discontinued after 3–4 months or pulse intravenous therapy is used instead (500–1000 mg of intravenous methylprednisolone sodium succinate for 3 consecutive days/month) [15, 20].

### **3. Morpheaform inflammatory syndromes/conditions**

Some diseases and disorders with acrosclerosis and Raynaud's phenomenon have a clinical presentation similar to localized scleroderma. The etiology of these disorders is diverse and includes, e.g., secondary sclerosis after exposition to bleomycin, vinyl chloride, L-tryptophan, or toxic oils. Sclerosis can also be induced by endogenous metabolites, by x-irradiation, or during chronic graft-versus-host disease (GVHD) (**Figure 9**). Morphea-like lesion, eosinophilic fasciitis, and lichen sclerosus can also be observed in these patients [21].

### **3.1 Lipodermatosclerosis**

### *3.1.1 Introduction*

Typical changes associated with chronic venous insufficiency include erythema, induration, and hemosiderin pigmentary changes. But a variety of clinical

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and obesity [23, 24].

**Figure 9.**

*sclerotic skin affecting the left thigh.*

*3.1.2 Clinical features*

*Systemic Sclerosis Mimics*

*DOI: http://dx.doi.org/10.5772/intechopen.88546*

appearances and histopathologic findings also include sclerosis, or sclerosing panniculitis. The various manifestations of this panniculitis have been consolidated

*Morphea-like lesion in a patient with GVHD. Post-inflammatory hyperpigmentation with whitish areas of* 

Lipodermatosclerosis typically manifests in patients, usually in women over the age of 40 years with chronic venous insufficiency as a result of chronic hypoxia. Venous hypertension leads to a compromised ability to reduce foot vein pressure during exercise. This change results in increased capillary permeability, with leakage of fibrinogen, with subsequent polymerization leading to formation of fibrin plaques around vessels. There may also be an abnormal regulation of angiogenesis in a patient with lipodermatosclerosis. For example, increased expression of vascular endothelial growth factor receptor 1 (VEGFR-1) can be a result of VEGFmediated angiogenesis. Another factors may include local stimulation of collagen

Sclerosis affects the acral parts of the lower limbs symmetrically. The acute and progressive phase of lipodermatosclerosis presents with pain, erythema, and the formation of induration on the affected area of lower limbs. In the chronic phase, sclerosis of the dermis and subcutis is typically present, and sclerosis results in induration that is more sharply demarcated from the adjacent normal skin (**Figure 10**). Other gravity dependent sites such as the lower aspect of the abdominal pannus can also develop lipodermatosclerosis. At this point, the changes are relatively diffuse. Hyperpigmentation due to hemosiderin deposition or chronic

ulceration of the lower limbs may also be present [22].

under the heading of lipodermatosclerosis or sclerosing panniculitis [22].

### **Figure 9.**

*New Insights into Systemic Sclerosis*

patients [15, 17].

**2.14 Systemic treatment**

consecutive days/month) [15, 20].

**3.1 Lipodermatosclerosis**

*3.1.1 Introduction*

**2.13 Topical and intralesional treatment**

effective in some patients with plaque-type morphea [18].

muscle) and should not be considered as primary therapy alone [19].

**3. Morpheaform inflammatory syndromes/conditions**

sclerosus can also be observed in these patients [21].

Topical therapies are unlikely to be effective for the disease involving the subcutis or deeper tissues and are not useful for preventing the development of new lesions in patients with rapidly progressive disease. Topical tacrolimus as tacrolimus 0.1% ointment may be effective for active, inflammatory morphea [16]. High potency topical and intralesional corticosteroids are widely used for the treatment of morphea; however, no formal studies have documented their efficacy. Topical vitamin D—vitamin D as topical calcipotriene 0.005% ointment—may inhibit effects on fibroblast proliferation, collagen synthesis, and T-cell activation. In some clinical studies, an improvement on this therapy was noted in limited numbers of

Imiquimod is a topical immunomodulator that induces interferon-gamma, a cytokine that inhibits TGF-beta and the production of extracellular matrix proteins. Imiquimod also downregulates the profibrotic cytokine IL-4. Limited data suggest that imiquimod is

It is possible to use phototherapy in patients with sclerotic diseases like morphea. Longer wavelengths of light as ultraviolet A (UVA) (320–400 nm) are capable of greater depth of penetration into the skin, and most studies of UV phototherapy in sclerotic skin disease have focused on the use of UVA light (320–400 nm). Fewer data are available on the use of PUVA therapy (a combination of UVA and topical or oral use of psoralens) and ultraviolet B (UVB) light (290–320 nm). Phototherapy is unlikely to be effective for morphea with deep involvement (subcutis, fascia, or

Patients with the progressive disease require systemic therapy with methotrexate or corticosteroids. Methotrexate is the most appropriate systemic therapy for morphea. In patients with acute generalized or rapidly progressive disease, we combine treatment with systemic corticosteroids. Methotrexate is typically given for at least 6–12 months with a weekly dose of 15–25 mg. The systemic corticosteroids are usually tapered and discontinued after 3–4 months or pulse intravenous therapy is used instead (500–1000 mg of intravenous methylprednisolone sodium succinate for 3

Some diseases and disorders with acrosclerosis and Raynaud's phenomenon have a clinical presentation similar to localized scleroderma. The etiology of these disorders is diverse and includes, e.g., secondary sclerosis after exposition to bleomycin, vinyl chloride, L-tryptophan, or toxic oils. Sclerosis can also be induced by endogenous metabolites, by x-irradiation, or during chronic graft-versus-host disease (GVHD) (**Figure 9**). Morphea-like lesion, eosinophilic fasciitis, and lichen

Typical changes associated with chronic venous insufficiency include erythema, induration, and hemosiderin pigmentary changes. But a variety of clinical

**94**

*Morphea-like lesion in a patient with GVHD. Post-inflammatory hyperpigmentation with whitish areas of sclerotic skin affecting the left thigh.*

appearances and histopathologic findings also include sclerosis, or sclerosing panniculitis. The various manifestations of this panniculitis have been consolidated under the heading of lipodermatosclerosis or sclerosing panniculitis [22].

Lipodermatosclerosis typically manifests in patients, usually in women over the age of 40 years with chronic venous insufficiency as a result of chronic hypoxia. Venous hypertension leads to a compromised ability to reduce foot vein pressure during exercise. This change results in increased capillary permeability, with leakage of fibrinogen, with subsequent polymerization leading to formation of fibrin plaques around vessels. There may also be an abnormal regulation of angiogenesis in a patient with lipodermatosclerosis. For example, increased expression of vascular endothelial growth factor receptor 1 (VEGFR-1) can be a result of VEGFmediated angiogenesis. Another factors may include local stimulation of collagen and obesity [23, 24].

### *3.1.2 Clinical features*

Sclerosis affects the acral parts of the lower limbs symmetrically. The acute and progressive phase of lipodermatosclerosis presents with pain, erythema, and the formation of induration on the affected area of lower limbs. In the chronic phase, sclerosis of the dermis and subcutis is typically present, and sclerosis results in induration that is more sharply demarcated from the adjacent normal skin (**Figure 10**). Other gravity dependent sites such as the lower aspect of the abdominal pannus can also develop lipodermatosclerosis. At this point, the changes are relatively diffuse. Hyperpigmentation due to hemosiderin deposition or chronic ulceration of the lower limbs may also be present [22].

### **Figure 10.**

*Lipodermatosclerosis in a patient with chronic venous insufficiency. In this case erythema and sclerotic whitish induration on the medial part of the shank with the border of hemosiderin pigmentary changes are present.*

### *3.1.3 Histopathology*

Early lesions show mid-lobular panniculitis, a lymphocytic infiltrate in the septa, variable degrees of capillary congestion, and extravasation of erythrocytes with hemosiderin deposition. Chronic lesions show septal sclerosis and membranocytic change with a marked reduction in inflammation or lymphocytic infiltrate [25, 26].

### *3.1.4 Differential diagnosis*

In differential diagnosis, it is necessary to distinguish inflammatory changes such as cellulitis and erysipelas but also erythema nodosum or erythema induratum. As induration develops and progresses, differentiation from morphea and scleromyxedema may be necessary. In morphea, subcutaneous involvement is predominantly septal, and lipophagic and lipodystrophic changes are not typically present [22, 25].

### *3.1.5 Treatment*

Leg elevation and consistent compression therapy are crucial for the treatment of lipodermatosclerosis. Traditional anti-inflammatory therapies are usually ineffective, but topical or intralesional corticosteroids (e.g., triamcinolone 5–10 mg/cc) may bring relief and improvement with compression therapy [27].

### **3.2 Injection of vitamin K**

Oil-soluble injection of vitamin K may be responsible for the eosinophilic reaction of the deep part of the dermis and subcutaneous fat, which may resemble localized eosinophilic fasciitis with similar clinical manifestation as deep morphea. This inflammation can result in dermal and subcutaneous atrophy [28].

### **3.3 Vaccination-associated morphea**

Circumscribed morphea and deep morphea have been described after intramuscular injections of different types of vaccines. The etiology and antigens responsible for this type of inflammation have not been reliably elucidated [29].

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quality of life.

*Systemic Sclerosis Mimics*

**3.5 Porphyrias**

**Figure 11.**

*lesion on the right breast.*

and upper part of the chest [31].

**3.6 Radiation-induced morphea**

years after radiation [32].

**3.7 Differential diagnosis**

**4. Lichen sclerosus**

organ involvement is crucial [21].

*DOI: http://dx.doi.org/10.5772/intechopen.88546*

**3.4 Paraffin and silicone injections or silicone implants**

or mixed connective tissue disease has also been discussed [30].

The leak of silicone from implants and silicone or paraffin injection after reconstructive or plastic surgery induce chronic inflammation that results in localized morphea-like lesion. The contribution to the induction of SSc, eosinophilic fasciitis,

*Morphea-like lesion in a patient after x-irradiation for breast carcinoma. The erythematous and sclerodermic* 

Porphyria cutanea tarda can lead to a morphea-like lesion and scarring in the chronic sun (UV)-exposed sites, such as the face, scalp, dorsal part of the hands,

X-irradiation can induce sclerotic, chronic erythematous, and secondary pigmented lesions typically in a patient after irradiation of the chest and axillary region for breast carcinoma (**Figure 11**). The morphea-like lesions can start several

The differential diagnosis is summarized in this paragraph, but the most important entity in the differential diagnosis of SSc or localized scleroderma is lichen sclerosus et atrophicus and scleromyxedema. Absence of overall symptoms and

Lichen sclerosus et atrophicus is an inflammatory disease, primarily of the superficial dermis or mucosa, which leads to white scar-like atrophy. Extragenital lichen sclerosus may itch and be cosmetically annoying. Genital lichen sclerosus causes dryness and persistent pruritus. Genital lichen leads to progressive atrophy, and functional impairment, which significantly reduces the

**Figure 11.**

*New Insights into Systemic Sclerosis*

*3.1.3 Histopathology*

**Figure 10.**

*3.1.4 Differential diagnosis*

**3.2 Injection of vitamin K**

**3.3 Vaccination-associated morphea**

*3.1.5 Treatment*

Early lesions show mid-lobular panniculitis, a lymphocytic infiltrate in the septa, variable degrees of capillary congestion, and extravasation of erythrocytes with hemosiderin deposition. Chronic lesions show septal sclerosis and membranocytic change

*Lipodermatosclerosis in a patient with chronic venous insufficiency. In this case erythema and sclerotic whitish induration on the medial part of the shank with the border of hemosiderin pigmentary changes are present.*

In differential diagnosis, it is necessary to distinguish inflammatory changes such as cellulitis and erysipelas but also erythema nodosum or erythema induratum. As induration develops and progresses, differentiation from morphea and scleromyxedema may be necessary. In morphea, subcutaneous involvement is predominantly septal, and lipophagic and lipodystrophic changes are not typically present [22, 25].

Leg elevation and consistent compression therapy are crucial for the treatment of lipodermatosclerosis. Traditional anti-inflammatory therapies are usually ineffective, but topical or intralesional corticosteroids (e.g., triamcinolone 5–10 mg/cc)

Oil-soluble injection of vitamin K may be responsible for the eosinophilic reaction of the deep part of the dermis and subcutaneous fat, which may resemble localized eosinophilic fasciitis with similar clinical manifestation as deep morphea.

Circumscribed morphea and deep morphea have been described after intramuscular injections of different types of vaccines. The etiology and antigens responsible

This inflammation can result in dermal and subcutaneous atrophy [28].

for this type of inflammation have not been reliably elucidated [29].

may bring relief and improvement with compression therapy [27].

with a marked reduction in inflammation or lymphocytic infiltrate [25, 26].

**96**

*Morphea-like lesion in a patient after x-irradiation for breast carcinoma. The erythematous and sclerodermic lesion on the right breast.*

### **3.4 Paraffin and silicone injections or silicone implants**

The leak of silicone from implants and silicone or paraffin injection after reconstructive or plastic surgery induce chronic inflammation that results in localized morphea-like lesion. The contribution to the induction of SSc, eosinophilic fasciitis, or mixed connective tissue disease has also been discussed [30].

### **3.5 Porphyrias**

Porphyria cutanea tarda can lead to a morphea-like lesion and scarring in the chronic sun (UV)-exposed sites, such as the face, scalp, dorsal part of the hands, and upper part of the chest [31].

### **3.6 Radiation-induced morphea**

X-irradiation can induce sclerotic, chronic erythematous, and secondary pigmented lesions typically in a patient after irradiation of the chest and axillary region for breast carcinoma (**Figure 11**). The morphea-like lesions can start several years after radiation [32].

### **3.7 Differential diagnosis**

The differential diagnosis is summarized in this paragraph, but the most important entity in the differential diagnosis of SSc or localized scleroderma is lichen sclerosus et atrophicus and scleromyxedema. Absence of overall symptoms and organ involvement is crucial [21].

### **4. Lichen sclerosus**

Lichen sclerosus et atrophicus is an inflammatory disease, primarily of the superficial dermis or mucosa, which leads to white scar-like atrophy. Extragenital lichen sclerosus may itch and be cosmetically annoying. Genital lichen sclerosus causes dryness and persistent pruritus. Genital lichen leads to progressive atrophy, and functional impairment, which significantly reduces the quality of life.

### **4.1 Epidemiology**

Prevalence of lichen sclerosus is unknown. This chronic disease occurs at all ages with a similar incidence in all races. The ratio of occurrence in men and women varies considerably, but in both sexes, the most affected area is the anogenital region (about 85% of patients, in women usually as a vulvar disease) [33, 34].

### **4.2 Pathogenesis**

Association with the MHC class II antigen HLA-DQ7 was observed, but the specific genetic predisposition is unknown. Unspecific inflammation seems to be essential for the initiation and also the progression of lichen sclerosus. Autoantibodies such as those against the extracellular matrix protein 1 (ECM-1) were found in 80% of patients with lichen sclerosus. Moreover, in female patients with lichen sclerosus, there is a higher prevalence of autoimmune diseases (especially autoimmune thyroid disease) and ANA positivity than in male patients with lichen sclerosus [34–36].

### **4.3 Clinical features**

Lichen sclerosus manifests by polygonal, bluish-white, shiny, slightly elevated maculopapules with a pointed follicular bounds of hyperkeratoses, which may be solitary or in groups. This skin lesion can be bounded with an area of erythema. The solitary lesion enlarges to plaques and to the scar-like lesion with a rough surface and skin atrophy (**Figure 12**).

More rarely, blistering with possible hemorrhagic content can be present (**Figure 13**). Extragenital predilection sites include supraclavicular localization, under the breasts, cubit, groin, loose wrist, and cross. Symptoms of extragenital lichen sclerosus are dryness and pruritus.

However, lichen sclerosus most frequently affects the anogenital region. In women, it typically affects the vulva and the perianal localization in figure-of-eight configuration (**Figure 14**). Genital lichen sclerosus begins as slightly elevated lesion of erythema, sometimes with erosions. During the chronic stage of the disease, the skin becomes shiny, sclerotic, and also hypopigmented. The scarring may affect the clitoris and labia, and disability may be significant or even make the sexual intercourse impossible. Although the disease may be symptom-free, it frequently causes severe pruritus and pain is a typical symptom. Another symptom may be dysuria or pain upon defecation [34, 37].

### **Figure 12.**

*Extragenital lichen sclerosus, slightly elevated plaque with scar-like presentation, with a whitish erythematous rim and skin atrophy.*

**99**

**4.4 Histopathology**

**Figure 14.**

sclerosus and is not observed in morphea [38–40].

Lichen sclerosus has a specific histopathological pattern. Initially, superficial dermal edema is associated with a band-like lymphocytic infiltrate. The epidermis is thinned and atrophic, with orthohyperkeratosis and vacuolar degeneration of the basal layer. Hyperkeratosis is especially pronounced at follicular openings and may lead to plugging. Vacuolar degeneration of the basal layer and flattening of the rete ridges predispose to the development of blisters, which may become hemorrhagic. The most important changes are found in the superficial dermis with the presence of homogenized collagen (**Figure 15**). Loss of elastic fibers is typical for lichen

*Genital lichen sclerosus affects the labia minora, clitoris, and vulval vestibule. Whitish and erythematous* 

*plaques are also present in the labia majora, the perineum, and the perianal region.*

*Extragenital lichen sclerosus, whitish plaque with blisters and crusts. Blisters resemble hemorrhagic-like content.*

*Systemic Sclerosis Mimics*

**Figure 13.**

*DOI: http://dx.doi.org/10.5772/intechopen.88546*

*Systemic Sclerosis Mimics DOI: http://dx.doi.org/10.5772/intechopen.88546*

### **Figure 13.**

*New Insights into Systemic Sclerosis*

Prevalence of lichen sclerosus is unknown. This chronic disease occurs at all ages with a similar incidence in all races. The ratio of occurrence in men and women varies considerably, but in both sexes, the most affected area is the anogenital region

Association with the MHC class II antigen HLA-DQ7 was observed, but the specific genetic predisposition is unknown. Unspecific inflammation seems to be essential for the initiation and also the progression of lichen sclerosus. Autoantibodies such as those against the extracellular matrix protein 1 (ECM-1) were found in 80% of patients with lichen sclerosus. Moreover, in female patients with lichen sclerosus, there is a higher prevalence of autoimmune diseases (especially autoimmune thyroid disease) and ANA positivity than in male patients with lichen sclerosus [34–36].

Lichen sclerosus manifests by polygonal, bluish-white, shiny, slightly elevated maculopapules with a pointed follicular bounds of hyperkeratoses, which may be solitary or in groups. This skin lesion can be bounded with an area of erythema. The solitary lesion enlarges to plaques and to the scar-like lesion with a rough surface

More rarely, blistering with possible hemorrhagic content can be present (**Figure 13**). Extragenital predilection sites include supraclavicular localization, under the breasts, cubit, groin, loose wrist, and cross. Symptoms of extragenital

However, lichen sclerosus most frequently affects the anogenital region. In women, it typically affects the vulva and the perianal localization in figure-of-eight configuration (**Figure 14**). Genital lichen sclerosus begins as slightly elevated lesion of erythema, sometimes with erosions. During the chronic stage of the disease, the skin becomes shiny, sclerotic, and also hypopigmented. The scarring may affect the clitoris and labia, and disability may be significant or even make the sexual intercourse impossible. Although the disease may be symptom-free, it frequently causes severe pruritus and pain is a typical symptom. Another symptom may be dysuria or

*Extragenital lichen sclerosus, slightly elevated plaque with scar-like presentation, with a whitish erythematous* 

(about 85% of patients, in women usually as a vulvar disease) [33, 34].

**4.1 Epidemiology**

**4.2 Pathogenesis**

**4.3 Clinical features**

and skin atrophy (**Figure 12**).

pain upon defecation [34, 37].

lichen sclerosus are dryness and pruritus.

**98**

**Figure 12.**

*rim and skin atrophy.*

*Extragenital lichen sclerosus, whitish plaque with blisters and crusts. Blisters resemble hemorrhagic-like content.*

### **Figure 14.**

*Genital lichen sclerosus affects the labia minora, clitoris, and vulval vestibule. Whitish and erythematous plaques are also present in the labia majora, the perineum, and the perianal region.*

### **4.4 Histopathology**

Lichen sclerosus has a specific histopathological pattern. Initially, superficial dermal edema is associated with a band-like lymphocytic infiltrate. The epidermis is thinned and atrophic, with orthohyperkeratosis and vacuolar degeneration of the basal layer. Hyperkeratosis is especially pronounced at follicular openings and may lead to plugging. Vacuolar degeneration of the basal layer and flattening of the rete ridges predispose to the development of blisters, which may become hemorrhagic. The most important changes are found in the superficial dermis with the presence of homogenized collagen (**Figure 15**). Loss of elastic fibers is typical for lichen sclerosus and is not observed in morphea [38–40].

**Figure 15.**

*Skin biopsy of extragenital lichen sclerosus where atrophic thinned epidermis and mild vacuolar degeneration of the basal layer are present. In the superficial dermis, homogenized collagen with perivascular lymphocytic infiltrates can be found.*

### **4.5 Differential diagnosis**

The differential diagnosis of extragenital lichen sclerosus includes morphea, vitiligo, tinea versicolor, anetoderma, or cutaneous lymphoma. In the case of genital lichen sclerosus, erosive lichen planus and erythroplasia of Queyrat must be considered.

Sometimes it is not possible to distinguish morphea from lichen because clinical and especially histopathological findings of both diseases can also be present in one patient or one biopsy [34].

### **4.6 Treatment**

Topical medications, phototherapy, and systemic therapy have been used for the treatment of lichen sclerosus. The effect of topical corticosteroids was reported especially in genital lichen sclerosus, but mitigation has also been demonstrated in extragenital lichen. Effect of topical corticosteroid therapy has been reported in randomized treatment and retrospective studies. Phototherapy is preferred second-line treatment for patients with limited disease that cannot be effectively treated with topical corticosteroids. An alternative to topical corticosteroids is the use of calcineurin inhibitors pimecrolimus and tacrolimus despite concerns of possible increase of development of squamous cell carcinoma or reactivation of HPV [15, 37, 41].

The use of systemic therapy is limited to a small group of patients with progressive worsening of extragenital lichen sclerosus that failed to respond to a potent topical corticosteroid and phototherapy. For systemic therapy, methotrexate (15–20 mg/week) and systemic corticosteroids (1 g of intravenous methylprednisolone sodium succinate for 3 consecutive days/month) can be used [42].

**101**

**Figure 16.**

*inflammatory appearance.*

*Systemic Sclerosis Mimics*

**5.1 Clinical feature**

**5.2 Histopathology**

normal width [44].

**5.3 Treatment**

**5. Eosinophilic fasciitis**

of the hands, feet, and face [43].

*DOI: http://dx.doi.org/10.5772/intechopen.88546*

Eosinophilic fasciitis is a relatively recently described disease, characterized by fibrosing induration of the extremities and peripheral eosinophilia. In many patients strenuous physical activity precedes the development of this condition.

Initial clinical manifestation includes painful edema of the extremities, which progresses to fibrosis and pseudo-inflammatory appearance (**Figure 16**). The manifestation of the disease is typically symmetrical on extremities without involvement

Laboratory findings include elevation of ESR, hypergammaglobulinemia and peripheral eosinophilia which can be present in the early phase of the disease. ANA titer and complement level are usually normal. Pancytopenia, anemia, thrombocytopenia, myeloproliferative disorders, and monoclonal gammopathy have been reported in association with eosinophilic fasciitis. The diagnosis of eosinophilic

Histologically eosinophils and mast cells are present, and dermal fibrosis with patchy infiltrates composed of lymphocytes and plasma cells are also present. In deep biopsy thickening of the fascia is typical, which may be 10–50 times the

Once the diagnosis of eosinophilic fasciitis is established via fascial biopsy and/ or MRI, prompt treatment is essential to preserve mobility and function and prevent joint contractures. Prompt therapy with oral corticosteroids (e.g., prednisone 1–2 mg/kg daily) is usually necessary for reduction or cessation of rapid disease progression and as prevention of mobility reduction and development of joint contractures. The response is typically noted within the first few weeks, and clinical improvement may be seen over several months. Alternatively, hydroxychloroquine, cyclosporine, dapsone, methotrexate, PUVA, or infliximab may be used alone or in combination with prednisone. Phototherapy as UVA1 can also be beneficial [45].

*Eosinophilic fasciitis with initial clinical manifestation of progressive fibrotic changes with pseudo-*

fasciitis is established via fascial biopsy and/or by MRI [44].
