**8.2 Clinical features**

In the clinical manifestation of scleromyxedema, typically widespread and symmetrically firm, waxy, and closely aligned papules are present (**Figure 17**).

**Figure 17.** *Scleromyxedema. Numerous skin-colored papules of the neck.*

Predilection localizations include the head and neck, upper trunk, forearms, and thighs and the proximal parts of fingers. The surrounding skin is shiny with sclerodermoid appearance. Deep longitudinal furrowing is typically involved on the glabella. Strong and rigid infiltrates of the face can result in the face of a lionlike face. As the condition progresses, erythematous and infiltrated plaques may be present with skin stiffening, sclerodactyly, and decreased motility of the mouth and joints.

Scleromyxedema is almost always associated with paraproteinemia. The monoclonal gammopathy is usually IgG and the light chains are more commonly lambda. Patients with scleromyxedema can have a number of internal manifestations, such as dysphagia, proximal muscle weakness due to myositis, peripheral neuropathy, arthropathies, carpal tunnel syndrome, restrictive or obstructive lung disease, and also scleroderma-like renal disease [54].

### **8.3 Histopathology**

Scleromyxedema is characterized by diffuse deposits of mucin in the upper and middle part of the reticular dermis, increase in collagen deposition in the reticular dermis, and significant proliferation of irregularly distributed fibroblasts. Mucin may fill the walls of myocardial blood vessels as well as vessels of the kidney, the pancreas, adrenal glands, nerves, or lymph nodes [55].

### **8.4 Differential diagnosis**

The primary differential diagnosis of scleromyxedema includes systemic sclerosis and scleredema. Other conditions in differential diagnosis with possible presence of mucin in the biopsy include nephrogenic systemic sclerosis. Differential diagnosis of leonine facies includes, for example, lepromatous changes, leishmaniasis, cutaneous lymphoma (T cell, rarely B cell), an actinic reticuloid as chronic actinic dermatitis, systemic amyloidosis, nodular mastocytosis, or sarcoidosis [53].

### **8.5 Treatment**

Recommendations are still based on case reports and open-label small case series. Many chemotherapeutics, primarily melphalan, cyclophosphamide, methotrexate, or chlorambucil, have been tried, with no better results but with the risk of significant side effects. IVIg, alone or in combination with systemic medications such as thalidomide or systemic corticosteroids, may be administered as first-line therapy for cutaneous involvement and also systemic manifestations, including the dermatoneurological syndrome. Additional therapies include PUVA, UVA1, systemic retinoids, cyclosporine, electron beam radiation, plasmapheresis, and extracorporeal photochemotherapy with variable and unpredictable results [56].

### **9. Scleredema adultorum of Buschke**

Scleredema is typically symmetrical diffuse induration and sclerosis of the upper part of the body especially of the trunk due to thickened dermis with mucin deposition and with relationship to diabetes mellitus.

### **9.1 Pathogenesis**

Scleredema is a relatively unusual and rare disease that affects patients of all races. The typical form that is associated with diabetes mellitus is more prevalent in

**105**

**Figure 18.**

*erythematous and indurated skin.*

*Systemic Sclerosis Mimics*

**9.2 Clinical features**

**9.3 Histopathology**

the skeletal muscle and in the heart.

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

ated with a monoclonal gammopathy [58].

and cardiac abnormalities may be present [57–59].

men, while other forms are seen more commonly in women. Irreversible glycosylation of collagen and resistance to degradation lead to an accumulation of collagen deposition. Furthermore, stimulation by insulin, microvascular changes and damage, and hypoxia during diabetes mellitus may increase the synthesis of collagen

Scleredema adultorum may be divided into three clinical types of scleredema. The first type affects primarily children and middle-aged women. It is preceded by fever, malaise, and an infection (usually streptococcal) of the upper or lower respiratory tract. The localization of this type is the cervicofacial region with extension to the trunk and proximal upper limbs. The cervicofacial region typically affects the perioral localization with difficult opening of the mouth and hindered swallowing. This type usually resolves spontaneously. The second type shares the same clinical features as the first but with very slow manifestation and is more commonly associ-

The third type typically affects obese middle-aged men with insulin-dependent diabetes (scleredema diabeticorum). Sclerosis usually starts very slowly and the involvement is persistent. Affected skin is usually erythematous and indurated with typical localization of the posterior region of the neck and the back (**Figure 18**). The affected skin has peau d'orange appearance. In all three forms, systemic manifestations such as serositis, myositis, dysarthria, dysphagia, parotitis, and ocular

The main histopathological feature is the thickening of the reticular dermis, with atypical large collagen bundles. Mucin deposition is also present among separated collagen bundles. There is no increase in the number of fibroblasts, but the elastic fibers are significantly reduced in number. Mucin is also accumulated in

*Scleredema adultorum with typical localization of the posterior region of the neck and the back with affected* 

and mucin which result in a dermal deposition of collagen [57].

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

men, while other forms are seen more commonly in women. Irreversible glycosylation of collagen and resistance to degradation lead to an accumulation of collagen deposition. Furthermore, stimulation by insulin, microvascular changes and damage, and hypoxia during diabetes mellitus may increase the synthesis of collagen and mucin which result in a dermal deposition of collagen [57].

### **9.2 Clinical features**

*New Insights into Systemic Sclerosis*

also scleroderma-like renal disease [54].

**9. Scleredema adultorum of Buschke**

deposition and with relationship to diabetes mellitus.

pancreas, adrenal glands, nerves, or lymph nodes [55].

**8.3 Histopathology**

**8.4 Differential diagnosis**

**8.5 Treatment**

Predilection localizations include the head and neck, upper trunk, forearms, and thighs and the proximal parts of fingers. The surrounding skin is shiny with sclerodermoid appearance. Deep longitudinal furrowing is typically involved on the glabella. Strong and rigid infiltrates of the face can result in the face of a lionlike face. As the condition progresses, erythematous and infiltrated plaques may be present with skin stiffening, sclerodactyly, and decreased motility of the mouth and joints. Scleromyxedema is almost always associated with paraproteinemia. The monoclonal gammopathy is usually IgG and the light chains are more commonly lambda. Patients with scleromyxedema can have a number of internal manifestations, such as dysphagia, proximal muscle weakness due to myositis, peripheral neuropathy, arthropathies, carpal tunnel syndrome, restrictive or obstructive lung disease, and

Scleromyxedema is characterized by diffuse deposits of mucin in the upper and middle part of the reticular dermis, increase in collagen deposition in the reticular dermis, and significant proliferation of irregularly distributed fibroblasts. Mucin may fill the walls of myocardial blood vessels as well as vessels of the kidney, the

The primary differential diagnosis of scleromyxedema includes systemic sclerosis and scleredema. Other conditions in differential diagnosis with possible presence of mucin in the biopsy include nephrogenic systemic sclerosis. Differential diagnosis of leonine facies includes, for example, lepromatous changes, leishmaniasis, cutaneous lymphoma (T cell, rarely B cell), an actinic reticuloid as chronic actinic dermatitis, systemic amyloidosis, nodular mastocytosis, or sarcoidosis [53].

Recommendations are still based on case reports and open-label small case series. Many chemotherapeutics, primarily melphalan, cyclophosphamide, methotrexate, or chlorambucil, have been tried, with no better results but with the risk of significant side effects. IVIg, alone or in combination with systemic medications such as thalidomide or systemic corticosteroids, may be administered as first-line therapy for cutaneous involvement and also systemic manifestations, including the dermatoneurological syndrome. Additional therapies include PUVA, UVA1, systemic retinoids, cyclosporine, electron beam radiation, plasmapheresis, and extracorporeal photochemotherapy with variable and unpredictable results [56].

Scleredema is typically symmetrical diffuse induration and sclerosis of the upper part of the body especially of the trunk due to thickened dermis with mucin

Scleredema is a relatively unusual and rare disease that affects patients of all races. The typical form that is associated with diabetes mellitus is more prevalent in

**104**

**9.1 Pathogenesis**

Scleredema adultorum may be divided into three clinical types of scleredema. The first type affects primarily children and middle-aged women. It is preceded by fever, malaise, and an infection (usually streptococcal) of the upper or lower respiratory tract. The localization of this type is the cervicofacial region with extension to the trunk and proximal upper limbs. The cervicofacial region typically affects the perioral localization with difficult opening of the mouth and hindered swallowing. This type usually resolves spontaneously. The second type shares the same clinical features as the first but with very slow manifestation and is more commonly associated with a monoclonal gammopathy [58].

The third type typically affects obese middle-aged men with insulin-dependent diabetes (scleredema diabeticorum). Sclerosis usually starts very slowly and the involvement is persistent. Affected skin is usually erythematous and indurated with typical localization of the posterior region of the neck and the back (**Figure 18**). The affected skin has peau d'orange appearance. In all three forms, systemic manifestations such as serositis, myositis, dysarthria, dysphagia, parotitis, and ocular and cardiac abnormalities may be present [57–59].

### **9.3 Histopathology**

The main histopathological feature is the thickening of the reticular dermis, with atypical large collagen bundles. Mucin deposition is also present among separated collagen bundles. There is no increase in the number of fibroblasts, but the elastic fibers are significantly reduced in number. Mucin is also accumulated in the skeletal muscle and in the heart.

### **Figure 18.**

*Scleredema adultorum with typical localization of the posterior region of the neck and the back with affected erythematous and indurated skin.*

### **9.4 Treatment**

Scleredema which is associated with streptococcal infections is self-limited, thus no therapy is needed. Therapy of scleredema associated with diabetes or a monoclonal gammopathy is more difficult, and no specific treatment is available. Phototherapy as UVA1 or PUVA is the first-line therapy. Systemic and intralesional corticosteroids, intralesional hyaluronidase, antibiotics, methotrexate, cyclosporine, pulse therapy with cyclophosphamide plus oral corticosteroids, tamoxifen, and allopurinol have all been tried, with variable results [58, 59].

### **10. Endocrine disorders**

Some endocrine disorders like diabetes mellitus and hypothyroidism can be accompanied with skin induration and sclerotic changes and may thus be a diagnostic problem for both systemic sclerosis and its localized forms. Endocrine disorders include sclerodactyly as "diabetic cheiroarthropathy" and myxedema in hypothyroidism.

### **10.1 Diabetic cheiroarthropathy**

Diabetes mellitus is associated with a wide variety of rheumatologic manifestations which can significantly affect a patient's quality of life. One of these manifestations includes diabetic cheiroarthropathy which is associated with type I diabetes. Diabetic cheiroarthropathy affects typically the hands. It is postulated to result from increased glycosylation of collagen in the skin and is associated with retinopathy, nephropathy, and duration of the diabetes [60, 61].

### *10.1.1 Clinical features*

Clinical features include thickened skin and limited joint mobility of the hands and fingers, leading to flexion contractures and an inability to approximate the palmar surfaces of the hands and fingers. Sometimes ischemic ulceration and calcinosis cutis can be present.

Treatment relies primarily on glycemic control and on nonsteroidal antiinflammatory drugs and physical therapy with physiotherapy. With improved glycemic control, the symptoms and signs can be ameliorated and complete reversal is possible [61].

### **10.2 Mucinoses associated with thyroid dysfunction**

Pretibial myxedema is characterized by cutaneous induration of the shins due to mucin deposition. It is often associated with hyperthyroidism most commonly due to Graves' disease. Localized myxedema with goiter, exophthalmos, and thyroid acropachy are typical signs of Graves' disease. Pretibial myxedema is found in 1–5% of patients with Graves' disease and in up to 25% of those with exophthalmos [62].

### *10.2.1 Localized myxedema*

### *10.2.1.1 Clinical features*

Localized myxedema presents as erythematous, yellowish or skin-colored waxy induration in a form of a nodulus or plaques. Typical localizations include ventral or

**107**

*10.2.1.2 Treatment*

**Figure 19.**

may have some benefit [63, 65].

*10.2.2 Generalized myxedema*

*10.2.2.1 Clinical features*

*Systemic Sclerosis Mimics*

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

anterolateral parts of the lower legs or the feet (**Figure 19**). In early phases localized myxedema can also present as a diffuse non-pitting edema of the shins or feet that evolves into lymphedema. Even more rarely, localized myxedema affects the face, shoulders, upper extremities, the lower abdomen, scars, or donor graft sites. Large plaques are often painful and pruritic. When present, hypertrichosis and hyperhi-

*Pretibial myxedema presents as erythematous waxy induration and nodulus on the ventral part of the shank.*

First-line therapy such as topical corticosteroids or their application under occlusive dressings can be used. In some cases intralesional injection of corticosteroids can be effective. In a patient with lymphedema, medical treatments including IVIg, rituximab, plasmapheresis, and their combination with surgical treatment

Generalized myxedema is a manifestation of hypothyroidism where mucin is deposited in the dermis, leading to waxiness of the skin. This condition is caused by a quantitative or functional deficiency of thyroxine. Impaired degradation of mucin

The typical skin is pale, cool, waxy, and dry. Anhidrosis as an absence of sweating may lead to ichthyosis or eczema "craquelé." Hair and nails are dry and diffuse

drosis are confined to the pretibial myxedematous skin [63, 64].

and/or increased synthesis is suggested as the main cause.

*New Insights into Systemic Sclerosis*

**10. Endocrine disorders**

**10.1 Diabetic cheiroarthropathy**

*10.1.1 Clinical features*

is possible [61].

exophthalmos [62].

*10.2.1 Localized myxedema*

*10.2.1.1 Clinical features*

calcinosis cutis can be present.

Scleredema which is associated with streptococcal infections is self-limited, thus no therapy is needed. Therapy of scleredema associated with diabetes or a monoclonal gammopathy is more difficult, and no specific treatment is available. Phototherapy as UVA1 or PUVA is the first-line therapy. Systemic and intralesional corticosteroids, intralesional hyaluronidase, antibiotics, methotrexate, cyclosporine, pulse therapy with cyclophosphamide plus oral corticosteroids, tamoxifen,

Some endocrine disorders like diabetes mellitus and hypothyroidism can be accompanied with skin induration and sclerotic changes and may thus be a diagnostic problem for both systemic sclerosis and its localized forms. Endocrine disorders include sclero-

Diabetes mellitus is associated with a wide variety of rheumatologic manifestations which can significantly affect a patient's quality of life. One of these manifestations includes diabetic cheiroarthropathy which is associated with type I diabetes. Diabetic cheiroarthropathy affects typically the hands. It is postulated to result from increased glycosylation of collagen in the skin and is associated with

Clinical features include thickened skin and limited joint mobility of the hands and fingers, leading to flexion contractures and an inability to approximate the palmar surfaces of the hands and fingers. Sometimes ischemic ulceration and

Treatment relies primarily on glycemic control and on nonsteroidal antiinflammatory drugs and physical therapy with physiotherapy. With improved glycemic control, the symptoms and signs can be ameliorated and complete reversal

Pretibial myxedema is characterized by cutaneous induration of the shins due to mucin deposition. It is often associated with hyperthyroidism most commonly due to Graves' disease. Localized myxedema with goiter, exophthalmos, and thyroid acropachy are typical signs of Graves' disease. Pretibial myxedema is found in 1–5% of patients with Graves' disease and in up to 25% of those with

Localized myxedema presents as erythematous, yellowish or skin-colored waxy induration in a form of a nodulus or plaques. Typical localizations include ventral or

and allopurinol have all been tried, with variable results [58, 59].

dactyly as "diabetic cheiroarthropathy" and myxedema in hypothyroidism.

retinopathy, nephropathy, and duration of the diabetes [60, 61].

**10.2 Mucinoses associated with thyroid dysfunction**

**9.4 Treatment**

**106**

**Figure 19.** *Pretibial myxedema presents as erythematous waxy induration and nodulus on the ventral part of the shank.*

anterolateral parts of the lower legs or the feet (**Figure 19**). In early phases localized myxedema can also present as a diffuse non-pitting edema of the shins or feet that evolves into lymphedema. Even more rarely, localized myxedema affects the face, shoulders, upper extremities, the lower abdomen, scars, or donor graft sites. Large plaques are often painful and pruritic. When present, hypertrichosis and hyperhidrosis are confined to the pretibial myxedematous skin [63, 64].

### *10.2.1.2 Treatment*

First-line therapy such as topical corticosteroids or their application under occlusive dressings can be used. In some cases intralesional injection of corticosteroids can be effective. In a patient with lymphedema, medical treatments including IVIg, rituximab, plasmapheresis, and their combination with surgical treatment may have some benefit [63, 65].

### *10.2.2 Generalized myxedema*

Generalized myxedema is a manifestation of hypothyroidism where mucin is deposited in the dermis, leading to waxiness of the skin. This condition is caused by a quantitative or functional deficiency of thyroxine. Impaired degradation of mucin and/or increased synthesis is suggested as the main cause.

### *10.2.2.1 Clinical features*

The typical skin is pale, cool, waxy, and dry. Anhidrosis as an absence of sweating may lead to ichthyosis or eczema "craquelé." Hair and nails are dry and diffuse

non-scaring alopecia is also common. A yellowish hyperkeratosis of the palms may be present. Sometimes purpura on the extremities and skin xanthomas may be observed [66].

### *10.2.2.2 Treatment*

Early treatment of hypothyroidism is crucial for reduction or cessation of skin involvement and overall symptoms of the disease.

### **11. Amyloidosis**

The cutaneous amyloidosis represents a heterogeneous group of conditions in which amyloid, as a fibrillar material that can result from the pathological degradation of various proteins, is deposited in the skin. In primary cutaneous amyloidosis, the deposits are derived from keratin (macular, lichen, biphasic) or immunoglobulin light chains (nodular) [67].

The specific cutaneous lesions of primary systemic amyloidosis are waxy, translucent, or purpuric papules, nodules, and plaques. Amyloid infiltration of the skin may produce thickening and stiffness. Typical localization may be on the limbs but sometimes also on the trunk. This is characteristic of AL amyloid, due to a plasma cell disorder in hematological malignancies. Primary systemic amyloidosis is due to a plasma cell dyscrasia, while secondary systemic amyloidosis arises from chronic inflammatory conditions such as rheumatoid arthritis or in the setting of chronic infections [67, 68].

Skin biopsy reveals accumulation of amyloid with characteristic staining (Congo red) properties under polarizing microscopic examination. Immunofixation of serum or urine is necessary for unambiguous identification of a monoclonal component [69].

Treatment of all forms of amyloidosis is challenging; although the primary cutaneous forms are not life-threatening, primary systemic amyloidosis can carry a poor prognosis for a patient [70].

### **12. Conclusion**

Systemic sclerosis mimics include a variety of diseases that may resemble systemic connective tissue diseases such as SSc. Above all, the most common diseases are discussed in this chapter.

The basis of proper diagnosis and treatment is the interdisciplinary collaboration of rheumatology and dermatology with the possibility of biopsy tissue collection and histological verification of the disease.

A carefully performed clinical history and physical examination may distinguish these scleroderma mimic syndromes from systemic sclerosis (SSc, scleroderma) and from each other. The distribution and the quality/texture of skin involvement (in SSc typically: sclerodactyly, puffy fingers, ischemic defects/pitting scars/ digital ulcers/gangrenes, telangiectasias, calcinosis), the presence of Raynaud's phenomenon (typically signs of a secondary Raynaud's phenomenon such as onset after the age of 40, asymmetry, thumb involvement, ischemic pain, history of symptoms <3 years, worsening attacks) or abnormal nail fold capillary microscopy (characteristic scleroderma patterns in SSc), the presence and type of associated systemic manifestations (typical organ involvement characteristic for SSc), and the association with particular concurrent diseases or specific laboratory parameters (SSc-specific autoantibodies such as anti-topoisomerase I, anti-centromere, anti-RNA-polymerase III) can be of substantial help in refining the diagnosis.

**109**

*Systemic Sclerosis Mimics*

tion of prognosis [71].

**Acknowledgements**

312218.

**Author details**

Czech Republic

Ondřej Kodet1,2,3\* and Sabína Oreská4

Charles University, Prague, Czech Republic

Medicine, Charles University, Prague, Czech Republic

\*Address all correspondence to: ondrej.kodet@vfn.cz

provided the original work is properly cited.

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

In some cases, a full-thickness skin biopsy is helpful to confirm the clinical suspicion. Effective therapies are available for some of these conditions, whereas others are more refractory. For this reason, a prompt diagnosis is important to guide treatment decisions wisely, to spare the patients from ineffective treatments, to facilitate appropriate diagnostic evaluations, and to allow for accurate determina-

This chapter was supported by NV18-01-00161 A, MHCR 023728 and GAUK

1 Department of Dermatology and Venereology, First Faculty of Medicine,

2 Institute of Anatomy, First Faculty of Medicine, Charles University, Prague,

3 BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

4 Institute of Rheumatology, Department of Rheumatology, First Faculty of

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

In some cases, a full-thickness skin biopsy is helpful to confirm the clinical suspicion. Effective therapies are available for some of these conditions, whereas others are more refractory. For this reason, a prompt diagnosis is important to guide treatment decisions wisely, to spare the patients from ineffective treatments, to facilitate appropriate diagnostic evaluations, and to allow for accurate determination of prognosis [71].

### **Acknowledgements**

*New Insights into Systemic Sclerosis*

involvement and overall symptoms of the disease.

observed [66].

*10.2.2.2 Treatment*

**11. Amyloidosis**

lin light chains (nodular) [67].

poor prognosis for a patient [70].

are discussed in this chapter.

tion and histological verification of the disease.

**12. Conclusion**

non-scaring alopecia is also common. A yellowish hyperkeratosis of the palms may be present. Sometimes purpura on the extremities and skin xanthomas may be

Early treatment of hypothyroidism is crucial for reduction or cessation of skin

The cutaneous amyloidosis represents a heterogeneous group of conditions in which amyloid, as a fibrillar material that can result from the pathological degradation of various proteins, is deposited in the skin. In primary cutaneous amyloidosis, the deposits are derived from keratin (macular, lichen, biphasic) or immunoglobu-

The specific cutaneous lesions of primary systemic amyloidosis are waxy, translucent, or purpuric papules, nodules, and plaques. Amyloid infiltration of the skin may produce thickening and stiffness. Typical localization may be on the limbs but sometimes also on the trunk. This is characteristic of AL amyloid, due to a plasma cell disorder in hematological malignancies. Primary systemic amyloidosis is due to a plasma cell dyscrasia, while secondary systemic amyloidosis arises from chronic inflammatory conditions such as rheumatoid arthritis or in the setting of chronic infections [67, 68]. Skin biopsy reveals accumulation of amyloid with characteristic staining (Congo red) properties under polarizing microscopic examination. Immunofixation of serum or urine is necessary for unambiguous identification of a monoclonal component [69]. Treatment of all forms of amyloidosis is challenging; although the primary cutaneous forms are not life-threatening, primary systemic amyloidosis can carry a

Systemic sclerosis mimics include a variety of diseases that may resemble systemic connective tissue diseases such as SSc. Above all, the most common diseases

The basis of proper diagnosis and treatment is the interdisciplinary collaboration of rheumatology and dermatology with the possibility of biopsy tissue collec-

A carefully performed clinical history and physical examination may distinguish these scleroderma mimic syndromes from systemic sclerosis (SSc, scleroderma) and from each other. The distribution and the quality/texture of skin involvement (in SSc typically: sclerodactyly, puffy fingers, ischemic defects/pitting scars/ digital ulcers/gangrenes, telangiectasias, calcinosis), the presence of Raynaud's phenomenon (typically signs of a secondary Raynaud's phenomenon such as onset after the age of 40, asymmetry, thumb involvement, ischemic pain, history of symptoms <3 years, worsening attacks) or abnormal nail fold capillary microscopy (characteristic scleroderma patterns in SSc), the presence and type of associated systemic manifestations (typical organ involvement characteristic for SSc), and the association with particular concurrent diseases or specific laboratory parameters (SSc-specific autoantibodies such as anti-topoisomerase I, anti-centromere, anti-

RNA-polymerase III) can be of substantial help in refining the diagnosis.

**108**

This chapter was supported by NV18-01-00161 A, MHCR 023728 and GAUK 312218.

### **Author details**

Ondřej Kodet1,2,3\* and Sabína Oreská4

1 Department of Dermatology and Venereology, First Faculty of Medicine, Charles University, Prague, Czech Republic

2 Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, Czech Republic

3 BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic

4 Institute of Rheumatology, Department of Rheumatology, First Faculty of Medicine, Charles University, Prague, Czech Republic

\*Address all correspondence to: ondrej.kodet@vfn.cz

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
