Scleroderma

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Scleroderma
MercMorphea.JPG
A type of localized scleroderma known as morphea
Specialty Rheumatology
Usual onsetMiddle age [1]
TypesLocalized, systemic scleroderma [2]
CausesUnknown [2]
Risk factors Family history, certain genetic factors, exposure to silica [3] [4] [5]
Diagnostic method Based on symptoms, skin biopsy, blood tests [6]
Differential diagnosis Mixed connective tissue disease, systemic lupus erythematosus, polymyositis, dermatomyositis [1]
Treatment Supportive care [1]
Medication Corticosteroids, methotrexate, non-steroidal anti-inflammatory drugs (NSAIDs) [2]
Prognosis Localized: Normal life expectancy [7]
Systemic: Decreased life expectancy [3]
Frequency3 per 100,000 per year (systemic) [3]

Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. [2] [6] [8] The disease can be either localized to the skin or involve other organs, as well. [2] Symptoms may include areas of thickened skin, stiffness, feeling tired, and poor blood flow to the fingers or toes with cold exposure. [1] One form of the condition, known as CREST syndrome, classically results in calcium deposits, Raynaud's syndrome, esophageal problems, thickening of the skin of the fingers and toes, and areas of small, dilated blood vessels. [1]

Contents

The cause is unknown, but it may be due to an abnormal immune response. [2] Risk factors include family history, certain genetic factors, and exposure to silica. [3] [4] [5] The underlying mechanism involves the abnormal growth of connective tissue, which is believed to be the result of the immune system attacking healthy tissues. [6] Diagnosis is based on symptoms, supported by a skin biopsy or blood tests. [6]

While no cure is known, treatment may improve symptoms. [2] Medications used include corticosteroids, methotrexate, and non-steroidal anti-inflammatory drugs (NSAIDs). [2] Outcome depends on the extent of disease. [3] Those with localized disease generally have a normal life expectancy. [7] In those with systemic disease, life expectancy can be affected, and this varies based on subtype. [3] Death is often due to lung, gastrointestinal, or heart complications. [3]

About three per 100,000 people per year develop the systemic form. [3] The condition most often begins in middle age. [1] Women are more often affected than men. [1] Scleroderma symptoms were first described in 1753 by Carlo Curzio [9] and then well documented in 1842. [10] The term is from the Greek skleros meaning "hard" and derma meaning "skin". [11] [12]

Signs and symptoms

Arm of a person with scleroderma showing skin lesions Left Arm Scleroderma Patient.jpg
Arm of a person with scleroderma showing skin lesions
Dark, shiny skin on distal phalanges of both hands in systemic sclerosis Systemic sclerosis, changes on hands are allways bilateral.jpg
Dark, shiny skin on distal phalanges of both hands in systemic sclerosis

Potential signs and symptoms include: [13] [14] [15]

Cause

Scleroderma is caused by genetic and environmental factors. [4] [5] [16] [17] Mutations in HLA genes seem to play a crucial role in the pathogenesis of some cases; likewise silica, aromatic and chlorinated solvents, ketones, trichloroethylene, welding fumes, and white spirits exposure seems to contribute to the condition in a small proportion of affected persons. [4] [5] [16] [17] [18]

Pathophysiology

Scleroderma is characterised by increased synthesis of collagen (leading to the sclerosis), damage to small blood vessels, activation of T lymphocytes, and production of altered connective tissue. [19] Its proposed pathogenesis is the following: [20] [21] [22] [23] [24]

Vitamin D is implicated in the pathophysiology of the disease. An inverse correlation between plasma levels of vitamin D and scleroderma severity has been noted, and vitamin D is known to play a crucial role in regulating (usually suppressing) the actions of the immune system. [26]

Diagnosis

Typical scleroderma is classically defined as symmetrical skin thickening, with about 70% of cases also presenting with Raynaud's phenomenon, nail-fold capillary changes, and antinuclear antibodies. Affected individuals may experience systemic organ involvement. No single test for scleroderma works all of the time, hence diagnosis is often a matter of exclusion. Atypical scleroderma may show any variation of these changes without skin changes or with finger swelling only. [27]

Laboratory testing can show antitopoisomerase antibodies, like anti-scl70 (causing a diffuse systemic form), or anticentromere antibodies (causing a limited systemic form and the CREST syndrome). Other autoantibodies can be seen, such as anti-U3 or anti-RNA polymerase. [28] Antidouble-stranded DNA autoantibodies are likely to be present in serum.[ citation needed ]

Differential

Diseases that are often in the differential include: [29]

Classification

Scleroderma is characterised by the appearance of circumscribed or diffuse, hard, smooth, ivory-colored areas that are immobile and which give the appearance of hidebound skin, a disease occurring in both localised and systemic forms: [30]

Treatment

No cure for scleroderma is known, although relief of symptoms is often achieved; these include treatment of: [13] [31]

Systemic disease-modifying treatment with immunosuppressants is often used. [16] [32] [33] [34] [35] [36] Immunosuppressants used in its treatment include azathioprine, methotrexate, cyclophosphamide, mycophenolate, intravenous immunoglobulin, rituximab, sirolimus, alefacept, and the tyrosine kinase inhibitors, imatinib, nilotinib, and dasatinib. [16] [31] [32] [33] [34] [35] [36] [37]

Experimental therapies under investigation include endothelin receptor antagonists, tyrosine kinase inhibitors, beta-glycan peptides, halofuginone, basiliximab, alemtuzumab, abatacept, and haematopoietic stem cell transplantation. [38] [39]

Immunomodulatory agents in the treatment of scleroderma
INN Mechanism of action [40] [41] Route of administration [40] Pregnancy category [40] [42] Major toxicities [40]
Alefacept Monoclonal antibody to inhibit T lymphocyte activation by binding to CD2 portion of human leukocyte function antigen-3.IMB (US)Malignancies, injection site reactions, blood clots, lymphopenia, hepatotoxicity and infections.
Azathioprine Purine analogue that inhibits lymphocyte proliferation via conversion to mercaptopurine PO, IVD (Au) Myelosuppression and rarely malignancy, hepatitis, infection, hepatic sinusoidal obstruction syndrome and hypersensitivity reactions.
Cyclophosphamide Nitrogen mustard that cross-links DNA base pairs, leading to breakages and triggering apoptosis in haematopoietic cells.PO, IVD (Au)Vomiting, myelosuppression, haemorrhagic cystitis and rarely heart failure, pulmonary fibrosis, hepatic sinusoidal obstruction syndrome, malignancy and SIADH
Dasatinib Tyrosine kinase inhibitor against various proangiogenic growth factors (including PDGF and VEGF).POD (Au)Fluid retention, myelosuppression, haemorrhage, infections, pulmonary hypertension, electrolyte anomalies and uncommonly hepatotoxicity, heart dysfunction/failure, myocardial infarction, QT interval prolongation, renal failure and hypersensitivity.
Imatinib As abovePOD (Au)As above and rarely: GI perforation, avascular necrosis and rhabdomyolysis
Immunoglobulin Immunoglobulin, modulates the immune system.IVN/AVaries
Methotrexate Antifolate; inhibits dihydrofolate reductase.PO, IV, IM, SC, ITD (Au)Myeosuppression, pulmonary toxicity, hepatotoxicity, neurotoxicity and rarely kidney failure, hypersensitivity reactions, skin and bone necrosis, and osteoporosis
Mycophenolate Inosine monophosphate dehydrogenase inhibitor, leading to reduced purine biosynthesis in lymphocytes.PO, IVD (Au)Myelosuppression, blood clots, less commonly GI perforation/haemorrhage and rarely pancreatitis, hepatitis, aplastic anaemia and pure red cell aplasia.
Nilotinib As per dasatinibPOD (Au)As per imatinib
Rituximab Monoclonal antibody against CD20, which is expressed on B lymphocytesIVC (Au)Infusion-related reactions, infection, neutropenia, reduced immunoglobulin levels, arrhythmias, less commonly anaemia, thrombocytopenia, angina, myocardial infarction, heart failure, and rarely haemolytic anaemia, aplastic anaemia, serum sickness, severe skin conditions, pulmonary infiltrates, pneumonitis, cranial neuropathy (vision or hearing loss) and progressive multifocal leucoencephalopathy.
Sirolimus mTOR inhibitor, thereby reducing cytokine-induced lymphocyte proliferation.POC (Au) Neutropenia, hypokalaemia, interstitial lung disease, pericardial effusion, pleural effusion, less commonly pulmonary haemorrhage, nephrotic syndrome, and rarely hepatotoxicity and lymphoedema.
PO = Oral. IV = Intravenous. IM = Intramuscular. SC = Subcutaneous. IT = Intrathecal.

The preferred pregnancy category, above, is Australian, if available. If unavailable, an American one is substituted.

Prognosis

As of 2012, the five-year survival rate for systemic scleroderma was about 85%, whereas the 10-year survival rate was just under 70%. [43] This varies according to the subtype; while localized scleroderma rarely results in death, the systemic form can, and the diffuse systemic form carries a worse prognosis than the limited form. The major scleroderma-related causes of death are: pulmonary hypertension, pulmonary fibrosis, and scleroderma renal crisis. [28] People with scleroderma are also at a heightened risk for developing osteoporosis and for contracting cancer (especially liver, lung, haematologic, and bladder cancers). [44] Scleroderma is also associated with an increased risk of cardiovascular disease. [45]

According to a study of an Australian cohort, between 1985 and 2015, the average life expectancy of a person with scleroderma increased from 66 years to 74 years (around 8 years less than the average Australian life expectancy of 82 years). [46]

Epidemiology

Scleroderma most commonly first presents between the ages of 20 and 50 years, although any age group can be affected. [13] [28] Women are four to nine times more likely to develop scleroderma than men. [28]

This disease is found worldwide. [28] In the United States, prevalence is estimated at 240 per million and the annual incidence of scleroderma is 19 per million people. [28] Likewise in the United States, it is slightly more common in African Americans than in their white counterparts. Choctaw Native Americans are more likely than Americans of European descent to develop the type of scleroderma that affects internal organs. [28] In Germany, the prevalence is between 10 and 150 per million people, and the annual incidence is between three and 28 per million people. [43] In South Australia, the annual incidence is 23 per million people, and the prevalence 233 per million people. [47]

Pregnancy

Scleroderma in pregnancy is a complex situation; it increases the risk to both mother and child. [48] Overall, scleroderma is associated with reduced fetal weight for gestational age. [48] The treatment for scleroderma often includes known teratogens such as cyclophosphamide, methotrexate, mycophenolate, etc., so careful avoidance of such drugs during pregnancy is advised. [48] In these cases hydroxychloroquine and low-dose corticosteroids might be used for disease control. [48]

See also

Related Research Articles

<span class="mw-page-title-main">Systemic scleroderma</span> Medical condition

Systemic scleroderma, or systemic sclerosis, is an autoimmune rheumatic disease characterised by excessive production and accumulation of collagen, called fibrosis, in the skin and internal organs and by injuries to small arteries. There are two major subgroups of systemic sclerosis based on the extent of skin involvement: limited and diffuse. The limited form affects areas below, but not above, the elbows and knees with or without involvement of the face. The diffuse form also affects the skin above the elbows and knees and can also spread to the torso. Visceral organs, including the kidneys, heart, lungs, and gastrointestinal tract can also be affected by the fibrotic process. Prognosis is determined by the form of the disease and the extent of visceral involvement. Patients with limited systemic sclerosis have a better prognosis than those with the diffuse form. Death is most often caused by lung, heart, and kidney involvement. The risk of cancer is increased slightly.

<span class="mw-page-title-main">Sjögren syndrome</span> Autoimmune disease affecting the bodys moisture-producing glands

Sjögren syndrome or Sjögren's syndrome is a long-term autoimmune disease that affects the body's moisture-producing glands, and often seriously affects other organ systems, such as the lungs, kidneys, and nervous system.

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura, systemic lupus erythematosus, Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, and multiple sclerosis. Autoimmune diseases are very often treated with steroids.

<span class="mw-page-title-main">Antinuclear antibody</span> Autoantibody that binds to contents of the cell nucleus

Antinuclear antibodies are autoantibodies that bind to contents of the cell nucleus. In normal individuals, the immune system produces antibodies to foreign proteins (antigens) but not to human proteins (autoantigens). In some cases, antibodies to human antigens are produced.

<span class="mw-page-title-main">Raynaud syndrome</span> Medical condition in which spasm of arteries causes episodes of reduced blood flow

Raynaud syndrome, also known as Raynaud's phenomenon, is a medical condition in which the spasm of small arteries causes episodes of reduced blood flow to end arterioles. Typically, the fingers, and less commonly, the toes, are involved. Rarely, the nose, ears, nipples, or lips are affected. The episodes classically result in the affected part turning white and then blue. Often, numbness or pain occurs. As blood flow returns, the area turns red and burns. The episodes typically last minutes but can last several hours. The condition is named after the physician Auguste Gabriel Maurice Raynaud, who first described it in his doctoral thesis in 1862.

<span class="mw-page-title-main">CREST syndrome</span> Medical condition

CREST syndrome, also known as the limited cutaneous form of systemic sclerosis (lcSSc), is a multisystem connective tissue disorder. The acronym "CREST" refers to the five main features: calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia.

<span class="mw-page-title-main">Morphea</span> Form of scleroderma involving isolated patches of hardened skin

Morphea is a form of scleroderma that mainly involves isolated patches of hardened skin on the face, hands, and feet, or anywhere else on the body, usually with no internal organ involvement. However, in Deep Morphea inflammation and sclerosis can be found in the deep dermis, panniculus, fascia, superficial muscle and bone.

Mixed connective tissue disease, commonly abbreviated as MCTD, is an autoimmune disease characterized by the presence of elevated blood levels of a specific autoantibody, now called anti-U1 ribonucleoprotein (RNP), together with a mix of symptoms of systemic lupus erythematosus (SLE), scleroderma, and polymyositis. The idea behind the "mixed" disease is that this specific autoantibody is also present in other autoimmune diseases such as systemic lupus erythematosus, polymyositis, scleroderma, etc. MCTD was characterized as an individual disease in 1972 by Sharp et al., and the term was introduced by Leroy in 1980.

Type V collagen is a form of fibrillar collagen associated with classical Ehlers-Danlos syndrome. It is found within the dermal/epidermal junction, placental tissues, as well as in association with tissues containing type I collagen.

Scleromyositis, is an autoimmune disease. People with scleromyositis have symptoms of both systemic scleroderma and either polymyositis or dermatomyositis, and is therefore considered an overlap syndrome. Although it is a rare disease, it is one of the more common overlap syndromes seen in scleroderma patients, together with MCTD and Antisynthetase syndrome. Autoantibodies often found in these patients are the anti-PM/Scl (anti-exosome) antibodies.

An overlap syndrome is a medical condition which shares features of at least two more widely recognised disorders. Examples of overlap syndromes can be found in many medical specialties such as overlapping connective tissue disorders in rheumatology, and overlapping genetic disorders in cardiology.

Anti-topoisomerase antibodies (ATA) are autoantibodies directed against topoisomerase and found in several diseases, most importantly scleroderma. Diseases with ATA are autoimmune disease because they react with self-proteins. They are also referred to as anti-DNA topoisomerase I antibody.

<span class="mw-page-title-main">Autoimmune inner ear disease</span> Medical condition

Autoimmune inner ear disease (AIED) was first defined by Dr. Brian McCabe in a landmark paper describing an autoimmune loss of hearing. The disease results in progressive sensorineural hearing loss (SNHL) that acts bilaterally and asymmetrically, and sometimes affects an individual's vestibular system. AIED is used to describe any disorder in which the inner ear is damaged as a result of an autoimmune response. Some examples of autoimmune disorders that have presented with AIED are Cogan's syndrome, relapsing polychondritis, systemic lupus erythematosus, granulomatosis with polyangiitis, polyarteritis nodosa, Sjogren's syndrome, and Lyme disease.

<span class="mw-page-title-main">Autoimmune disease</span> Disorders of adaptive immune system

An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated that there are more than 80 recognized autoimmune diseases, with recent scientific evidence suggesting the existence of potentially more than 100 distinct conditions. Nearly any body part can be involved.

<span class="mw-page-title-main">Systemic vasculitis</span> Medical condition

Necrotizing vasculitis, also called systemic necrotizing vasculitis, is a general term for the inflammation of veins and arteries that develops into necrosis and narrows the vessels.

<span class="mw-page-title-main">Lupus</span> Human autoimmune disease

Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common symptoms include painful and swollen joints, fever, chest pain, hair loss, mouth ulcers, swollen lymph nodes, feeling tired, and a red rash which is most commonly on the face. Often there are periods of illness, called flares, and periods of remission during which there are few symptoms.

Undifferentiated connective tissue disease (UCTD) is a disease in which the connective tissues are targeted by the immune system. It is a serological and clinical manifestation of an autoimmune disease. When there is proof of an autoimmune disease, it will be diagnosed as UCTD if the disease doesn't answer to any criterion of specific autoimmune disease. This is also the case of major rheumatic diseases whose early phase was defined by LeRoy et al. in 1980 as undifferentiated connective tissue disease.

<span class="mw-page-title-main">Anti-SSA/Ro autoantibodies</span> Type of anti-nuclear autoantibodies

Anti-SSA autoantibodies are a type of anti-nuclear autoantibodies that are associated with many autoimmune diseases, such as systemic lupus erythematosus (SLE), SS/SLE overlap syndrome, subacute cutaneous lupus erythematosus (SCLE), neonatal lupus and primary biliary cirrhosis. They are often present in Sjögren's syndrome (SS). Additionally, Anti-Ro/SSA can be found in other autoimmune diseases such as systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), rheumatoid arthritis (RA), and mixed connective tissue disease (MCTD), and are also associated with heart arrhythmia.

Autoimmunity refers to a pathological immune response of the body's immune system against itself. Autoimmune disease is widely recognized to be significantly more common in women than in men, and often presents differently between the sexes. The reasons for these disparities are still under investigation, but may in part involve the presence of an additional X chromosome in women, as well as the higher presence of female sex hormones such as estrogen. The risk, incidence, and character of autoimmune disease in women may also be associated with female-specific physiological changes, such as hormonal shifts during menses, pregnancy, and menopause.

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