Localized Fibrosing Disorders: Spectrum of Rare Skin Disorders

Introduction

Localized fibrosing disorders include a group of rare conditions that frequently starts in early childhood. The localized fibrosing disorders can be classified into several subtypes, which include morphea, generalized morphea, regional fibrosis, and linear scleroderma. Linear scleroderma and morphea can appear simultaneously in the same patient. The exact cause of localized fibrosing disorders are unknown, and the treatment varies with the specific condition.

There are various types of localized fibrosing disorders that get confused with systemic sclerosis, which include the following:

1. Localized scleroderma (morphea).

2. Drug-induced cutaneous reactions.

3. Scleredema.

4. Scleromyxedema.

5. Nephrogenic systemic fibrosis.

6. Chronic graft-versus-host disease.

What Is the Pathogenesis of Localized Fibrosing Disorders?

The exact pathogenesis of localized fibrosing disorders is unknown. However, autoimmune dysfunction (a condition in which the immune system of the body attacks its own cells) and extensive formation of extracellular matrix (collagen) are considered to be the prime causes of these disorders. The localized fibrosing disorders consist of multiple clinical and histopathological conditions that resemble the signs of skin involvement in systemic sclerosis, in which hardening and tightening of the skin occur. However, localized fibrosing disorders are characterized by circumscribed fibrotic areas due to excessive collagen (a protein found in skin, connective tissues, cartilage, and bones) synthesis.

The transforming growth factor-beta 1 (TGF-beta1) has been found to increase the synthesis of collagen and other extracellular matrix components in case of morphea and systemic sclerosis. However, the mechanism behind this has yet to be discovered.

In addition, multiple environmental factors have been found to cause morphea, such as skin friction, long-term pressure, or vaccination injections, constituting about 13 to 16 percent of morphea cases. It can also occur as a complication of radiation therapy.

What Is the Etiology of Localized Fibrosing Disorders?

The causes of localized fibrosing disorders are unknown. However, some of the suspected etiological factors include genetics, infections, and autoimmune dysfunction.

• Autoantibodies (an antibody produced in the immune system acting against its own cells) are commonly seen in localized scleroderma (morphea).

• Environmental factors such as radiation, ergot, and medications like Phenacetin, Hydralazine, and Propranolol can trigger these conditions.

• Infections such as varicella zoster, measles, Epstein-Barr virus infection, and borreliosis can develop fibrosing disorders.

• Vaccination such as BCG (Bacillus Calmette - Guérin) has also been reported to cause the development of morphea, and trauma has also been considered as a triggering factor in the development of these conditions.

What Are the Different Types of Localized Fibrosing Disorders?

Various types of localized fibrosing disorders get confused with systemic sclerosis, which include -

1. Morphea -

Morphea, also known as localized scleroderma, is an inflammatory condition characterized by increased collagen accumulation in the skin and subcutaneous tissues. Generally, the morphea skin changes appear on the abdomen, chest, or back of the body, but they can also appear on the face, arms, or legs. It usually affects the outermost layer of the skin and may also restrict the movement of joints.

Epidemiology -

Morphea is a rare disorder affecting 0.34 to 2.7 in 100,000 of the total population annually. It can affect all races and is most frequently seen in whites. It can be seen equally in children and adults. White linear morphea is most commonly seen in children, and plaque or circumscribed morphea is most commonly seen in adults.

Etiology -

Autoimmunity dysfunction plays an important role in causing morphea. Other than that, trauma, infection, and radiation therapy can also lead to this.

Types and Clinical Features of Morphea -

1. Plaque Morphea -

• Superficial - These are oval-shaped lesions limited to the epidermis and dermis. Mainly located in the trunk region.
• Deep - In this deep induration can be seen (hardening and thickening of the soft tissues) and is seen on the dermis and subcutaneous tissue.

2. Linear Morphea -

• Trunk and Limbs - This involves dermis and subcutaneous tissue and may affect bone and muscle also with linear induration.
• Head (linear scleroderma ‘en coup de saber) - Mostly present on the face and scalp and the tissues that can be involved in this are muscle, bone, and CNS (central nervous system).
• Progressive Facial Hemiatrophy - Tissues involved are the dermis, subcutaneous tissue, muscle, cartilage, and bone.

3. Generalized Morphea - In this hard and thickened plaques of size more than three centimeters can be seen and are limited to the dermis and rare in the subcutaneous tissue. Can be present anywhere on the body except the face or hands.

4. Mixed Morphea - Combination of two or more subtypes.

Diagnosis -

Morphea is usually diagnosed based on clinical features, but usually histopathologic examinations are required to confirm the diagnosis. For this biopsy can be done, which usually shows subcutaneous fat in the inflammatory phase along with various white blood cells such as lymphocytes, macrophages, plasma cells, eosinophils, and mast cells can be seen infiltrating the lesion. In addition, thickened, hyalinized collagen can also be seen in the fibrotic phase.

Treatment -

Various treatment options are available for patients with active lesions of morphea. However, the success rate of treatment is limited, and the treatment aims to stop the formation of new lesions and prevent the spread of disease. Various topical or systemic antipruritic agents can be used in cases of morphea, such as topical corticosteroids, topical Tacrolimus, Imiquimod five percent cream, vitamin D analogs, and UV radiation with or without 8-methoxy psoralen. In the case of generalized morphea, Infliximab, and Imatinib show promising results.

2. Scleredema -

Scleredema adultrum of Buschke is a disorder of connective tissue whose etiology is unknown and this disorder was discovered by Abraham Buschke. It is characterized by collagen deposition due to infections and poorly controlled diabetes.

Clinical Features -

Scleredema adultorum can be divided into three types which include the following:

• Type I - It affects children and middle-aged women. It shows symptoms like fever, malaise (discomfort or tiredness), and upper or lower respiratory tract infection. This type usually resolves on its own.

• Type II - This type shows the same clinical features as the first but is a slow, chronic, and progressive disease and is usually associated with monoclonal gammopathy of the IgG kappa type.

• Type III - This type affects male patients of age above 40 with long-standing poorly controlled diabetes and is known as scleredema diabeticorum.

Diagnosis -

Scleredema diagnosis is usually made clinically based on the extent of skin involvement and the nature of the associated conditions. Skin biopsy can be done in which thickening of the outer layer of skin can be seen up to four times more than normal. In addition, mucopolysaccharides can be seen in the wide spaces of swollen collagen fibers in tissues.

Treatment -

Antibiotics can be given to treat infections. In addition, immunosuppressive drugs such as corticosteroids, Methotrexate, Cyclosporine, and radiation therapy can treat scleredema.

3. Nephrogenic Systemic Fibrosis -

It is usually seen in middle-aged adults but also in children and old adults. Nephrogenic systemic fibrosis does not follow any race or gender preference. The disease developed due to renal dysfunction or exposure to a gadolinium-based contrast medium.

Clinical Features -

The large and indurated plaques can be seen on the extremities and trunk symmetrically. The skin lesions are erythematous and irregular, with the tendency to develop hyperpigmentation. Additionally, it can also cause pain and loss of mobility.

Treatment -

A biopsy is done to confirm the diagnosis and the treatment involves medication like immunosuppressive drugs and corticosteroids.

4. Scleromyxedema -

Scleromyxedema is a rare disorder mainly seen in people aged 30 to 80. It affects both genders equally and is also known as generalized lichen myxedematosus, first described by Dubreuilh in 1906, and Gottron gave the term scleromyxedema in 1954.

Clinical Features -

The characteristic features of scleromyxedema include small waxy, firm papules present on the face, neck, hands, distal forearms, and mucous membranes. It gives a lion-like face appearance with strong and rigid infiltrates of the face. As the condition progresses, erythematous and infiltrated plaques may be present, causing skin stiffening and decreased mouth and joint motility.

Diagnosis -

The four criteria by which scleromyxedema may be diagnosed include the following:

• A skin biopsy will show a histologic triad of mucin deposition, the proliferation of fibroblasts, and fibrosis.

• The presence of papules is a key feature that helps differentiate scleromyxedema from other conditions like morphea, scleredema, and systemic sclerosis.

• Generalized presence of papules and scleroderma cutaneous eruptions.

• Absence of thyroid dysfunction.

Treatment -

Topical therapies such as corticosteroids and UV (ultraviolet) light has been found to be effective. Other than that, drugs like Cyclophosphamide, Thalidomide, and Bortezomib can also be used.

5. Chronic Graft Versus Host Disease (cGVHD) -

This condition is seen in patients who receive an allogeneic stem cell or bone marrow transplant. An allogeneic transplant is a procedure in which a patient receives healthy blood-forming cells (stem cells) from a donor to replace impaired stem cells. Unfortunately, about 60 to 70 percent of patients who receive an allogeneic transplant will develop chronic graft versus host disease (cGVHD).

Clinical Features -

The thin white atrophic papules can be seen in this condition, usually on the trunk and extremities. Contractures and atrophy of the epidermis can lead to ulcerations in the legs and pretibial regions. In addition, cGVHD may also cause muscle weakness, pain, dry mouth, and ulcers, and there may be involvement of any organ of the body.

Treatment -

Systemic immunosuppressants such as systemic corticosteroids and mycophenolate can be given to treat this condition.

6. Drug-Induced Scleroderma-Like Illness -

There have been multiple reports of the development of scleroderma-like conditions due to certain drugs, which include the following:

• Pentazocine.

• Interferon beta1 a.

• Paclitaxel.

• Methysergide.

• Gemcitabine.

Conclusion

Localized fibrosing disorders are localized to the skin, but sometimes they cause systemic implications that require a proper diagnosis to treat these conditions. These disorders can mimic systemic sclerosis because of their resembling clinical features and fibrotic changes. Therefore careful clinical examination and medical history have to be taken to confirm the diagnosis. With understanding the pathogenesis of the disease and getting enough data on treatment therapies, managing these diseases can get easier.