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Scleroderma

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This article is about the disease. For the mushroom, see Scleroderma (fungus).
Not to be confused with scleredema.
Scleroderma
SpecialtyRheumatology, dermatology, immunology Edit this on Wikidata

Scleroderma, also known as systemic sclerosis, is a long term autoimmune disease that results in hardening of the skin. In the more severe form, it also affects internal organs.[1][2] The cause is unknown.[1] The underlying mechanism involves the body's immune system attacking healthy tissues.[1] There is a strong association with certain mutations in HLA genes.[3][4] Environmental factors have also been implicated.[5][6]

Limited scleroderma involves mainly the skin of the hands, arms and face. It was previously called CREST syndrome an acronym of the following common manifestations:[7] calcinosis (the deposition of calcium nodules in the skin), raynaud's phenomenon (exaggerated vasoconstriction in the hands, with fingers undergoing white-blue-red color transitions in the cold), esophageal dysfunction (leading to difficulty swallowing), sclerodactyly (skin thickening on the fingers), and telangiectasias (dilated capillaries on the face, hands and mucous membranes).

Diffuse scleroderma is rapidly progressing and affects a large area of the skin and one or more internal organs, frequently the kidneys, esophagus, heart and/or lungs. This form of scleroderma can be quite disabling. There are no treatments for scleroderma itself, but individual organ system complications are treated.[8][9]

Outcomes are generally good for limited scleroderma of the skin when there are no lung complications. They are worse for those with the diffuse skin disease, particularly in older age and males. Death occurs most often from lung, heart and kidney complications. In diffuse cutaneous disease, five-year survival is 70% and 10-year survival is 55%.[10] Scleroderma was first described in 1753 by Carlo Curzio of Ospedale degli Incurabili, Naples.[11]

Signs and symptoms

Left arm of a scleroderma sufferer, showing skin lesions

Potential signs and symptoms include:[2][7][10]

Cause

Scleroderma is caused by genetic and environmental factors.[3][4][5][6] Mutations in HLA genes seem to play a crucial role in the pathogenesis of some cases (but not all), 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.[3][4][5][6][12]

Pathophysiology

It 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 tissues.[13] Its proposed pathogenesis is the following:[14][15][16][17][18]

  • It begins with an inciting event at the level of the vasculature, probably the endothelium. The inciting event is yet to be elucidated but may be a viral agent, oxidative stress or autoimmune. Endothelial cell damage and apoptosis ensue, leading to the vascular leakiness that manifests in early clinical stages as tissue oedema. At this stage it is predominantly a Th1 and Th17-mediated disease.
  • After this the vasculature is further compromised by impaired angiogenesis and impaired vasculogenesis (fewer endothelial progenitor cells), likely related to the presence of anti-endothelin cell antibodies. Despite this impaired angiogenesis, elevated levels of pro-angiogenic growth factors like PDGF and VEGF is often seen in persons with the condition. The balance of vasodilation and vasoconstriction becomes off-balance and the net result is vasoconstriction. The damaged endothelium then serves as a point of origin for blood clot formation and further contributes to ischaemia-reperfusion injury and the generation of reactive oxygen species. These later stages are characterised by Th2 polarity.
  • The damaged endothelium upregulates adhesion molecules and chemokines to attract leucocytes, which enables the development of innate and adaptive immune responses, including loss of tolerance to various oxidised antigens, which includes topoisomerase I. B cells mature into plasma cells, which furthers the autoimmune component of the condition. T cells differentiate into subsets, including Th2 cells, which play a vital role in tissue fibrosis. Anti–topoisomerase 1 antibodies, in turn, stimulate type I interferon production.
  • Fibroblasts are recruited and activated by multiple cytokines and growth factors to generate myofibroblasts. Dysregulated transforming growth factor β (TGF-β) signalling in fibroblasts and myofibroblasts has been observed in multiple studies of scleroderma-affected individuals. Activation of fibroblasts and myofibroblasts leads to excessive deposition of collagen and other related proteins, leading to fibrosis. B cells are implicated in this stage, IL-6 and TGF-β produced by the B cells decrease collagen degradation and increase extracellular matrix production. Endothelin signalling is implicated in the pathophysiology of fibrosis.[19]

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.[20]

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 or may not experience systemic organ involvement. There is no single test for scleroderma that works all of the time and hence the diagnosis is often a matter of exclusion. Atypical scleroderma may show any variation of these changes without skin changes or with finger swelling only.[21]

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.[1]

Differential

Diseases that are often in the differential include:[22]

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:[23]

Treatment

There is no cure for scleroderma, although relief of symptoms is often achieved. These include[2][24]

Systemic disease-modifying treatment with immunosuppressants is often used.[3][25][26][27][28][29] Immunosuppressants used in its treatment include azathioprine, methotrexate, cyclophosphamide, mycophenolate, intravenous immunoglobulin, rituximab, sirolimus, alefacept and the tyrosine kinase inhibitors, imatinib, nilotinib and dasatinib.[3][24][25][26][27][28][29][30]

Experimental therapies under investigation include endothelin receptor antagonsits, tyrosine kinase inhibitors, beta-glycan peptides, halofuginone, basiliximab, alemtuzumab, abatacept and haematopoietic stem cell transplantation.[31][32]

Immunomodulatory agents in the treatment of scleroderma
INN Mechanism of action[33][34] Route of administration[33] Pregnancy category[33][35] Major toxicities[33]
Alefacept Monoclonal antibody to inhibit T lymphocyte activation by binding to CD2 portion of human leukocyte function antigen-3. IM B (US) Malignancies, injection site reactions, blood clots, lymphopenia, hepatotoxicity and infections.
Azathioprine Purine analogue that inhibits lymphocyte proliferation via conversion to mercaptopurine PO, IV D (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, IV D (Au) Vomiting, myelosuppression, haemorrhagic cystitis and rarely heart failure, pulmonary fibrosis, hepatic sinusoidal obstruction syndrome, malignancy and SIADH.
Dasatinib Tyrosine kinase inhibitor against various pro-angiogenic growth factors (including PDGF and VEGF). PO D (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 above. PO D (Au) As above and rarely: GI perforation, avascaular necrosis and rhabdomyolysis.
Immunoglobulin Immunoglobulin, modulates the immune system. IV N/A Varies.
Methotrexate Antifolate; inhibits dihydrofolate reductase. PO, IV, IM, SC, IT D (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, IV D (Au) Myelosuppression, blood clots, less commonly GI perforation/haemorrhage and rarely pancreatitis, hepatitis, aplastic anaemia and pure red cell aplasia.
Nilotinib As per dasatinib. PO D (Au) As per imatinib.
Rituximab Monoclonal antibody against CD20 which is expressed on B lymphocytes. IV C (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. PO C (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

The 5-year survival rate for scleroderma is about 85%, whereas the 10-year survival rate is less than 70%.[36] This varies according to the subtype; for instance, persons with limited skin disease have a 10-year survival rate of 71%, whereas the outlook for patients with systemic scleroderma has generally improved over the years. Ten-year survival rates rose from 54% in 1972 to 66% in 2001[37] The major causes of death in persons with scleroderma are: pulmonary hypertension, pulmonary fibrosis and scleroderma renal crisis.[1] People with scleroderma are also at a heightened risk for contracting cancers (especially liver, lung, haematologic and bladder cancers) and, perhaps, cardiovascular disease.[38][39][40][41][42]

Epidemiology

Scleroderma most commonly first presents between the ages of 20 and 50 years, although any age group can be affected.[1][2] Women are four to nine times more likely to develop scleroderma than men.[1]

This disease is found worldwide.[1] In the United States, prevalence is estimated at 240 per million and the annual incidence of scleroderma is 19 per million people.[1] Likewise in the United States, it is slightly more common in African Americans than in their white counterparts, Scleroderma occurs much more often in women than it does in men. Choctaw Native Americans are more likely than Americans of European descent to develop the type of scleroderma that affects internal organs.[1] In Germany, the prevalence is between 10 and 150 per million people, and the annual incidence is between 3 and 28 per million people.[36] In South Australia, the annual incidence is 23 per million people, and the prevalence 233 per million people.[43] Scleroderma is less common in the Asian population.[44]

Pregnancy

Scleroderma in pregnancy is a complex situation; it increases the risk to both mother and child.[45] Overall scleroderma is associated with reduced fetal weight for gestational age.[45] The treatment for scleroderma often includes known teratogens such as cyclophosphamide, methotrexate, mycophenolate, etc. and hence careful avoidance of such drugs during pregnancy is advised.[45] In these cases hydroxychloroquine and low-dose corticosteroids might be used for disease control.[45]

See also

References

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