|Classification and external resources|
Scleroderma, also known as systemic sclerosis, is a chronic systemic autoimmune disease characterised by hardening (sclero) of the skin (derma). In the more severe form, it also affects internal organs.
Limited scleroderma involves cutaneous manifestations that mainly affect the hands, arms and face. It was previously called CREST syndrome in reference to the following common manifestations: 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.
The prognosis is generally good for limited cutaneous scleroderma persons who escape pulmonary complications, but is worse for those with the diffuse cutaneous disease, particularly in older age and for males. Death occurs most often from pulmonary, heart and kidney complications. In diffuse cutaneous disease, five-year survival is 70% and 10-year survival is 55%.
The cause of scleroderma is unknown. It is an autoimmune condition, in which the body's immune system attacks healthy tissues. Strong associations with certain mutations in the HLA gene have been identified. Strong environment influences have also been implicated in the aetiology of scleroderma.
Signs and symptoms
- Cardiovascular: Raynaud's phenomenon (is the presenting symptom in 70% of affected persons, occurs in 95% of affected individuals at sometime during their illness); healed pitting ulcers on the fingertips; skin and mucousal telangiectasis; palpitations, irregular heart rate and syncope due to conduction abnormalities, hypertension and congestive heart failure.
- Digestive: gastro-oesophageal reflux disease, bloating, indigestion, loss of appetite, diarrhoea alternating with constipation, sicca syndrome and its complications, loosening of teeth and hoarseness (due to acid reflux).
- Pulmonary: progressive worsening of shortness of breath, chest pain (due to pulmonary artery hypertension) and dry, persistent cough due to interstitial lung disease.
- Musculoskeletal: joint, muscle aches, loss of joint range of motion, carpal tunnel syndrome and muscle weakness.
- Genitourinary: erectile dysfunction, dyspareunia, scleroderma renal crises and kidney failure.
- Other: facial pain due to trigeminal neuralgia, hand paraesthesias, headache, stroke, fatigue, calcinosis and weight loss.
The exact cause is yet to be fully elucidated; although the available data does support a genetic and environmental component to the condition. Mutations in the HLA gene seems 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.
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. Its proposed pathogenesis is the following:
- 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 both 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 various 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 also 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 also implicated in the pathophysiology of fibrosis.
Vitamin D is also implicated in the pathophysiology of the disease, for one 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.
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.
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.
Diseases that are often in the differential include:
- Eosinophilia, a condition in which there are too many eosinophils (a type of immune cell that attacks parasites and is involved in certain allergic reactions) in the blood.
- Eosinophilia-myalgia syndrome, a form of eosinophilia that is caused by L-tryptophan supplements.
- Eosinophilic fasciitis, a disease that affects the connective tissues surrounding skeletal muscles, bones, blood vessels and nerves in the arms and legs.
- Graft-versus-host disease, an autoimmune condition that occurs as a result of bone marrow transplants in which the old marrow attacks the new marrow.
- Mycosis fungoides, a type of cutaneous T cell lymphoma, a rare cancer that causes rashes all over the body.
- Nephrogenic systemic fibrosis, a condition usually caused by kidney failure that causes fibrosis (thickening) of the tissues.
- Primary biliary cirrhosis, an autoimmune disease of the liver.
- Primary pulmonary hypertension
- Complex regional pain syndrome
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:
- Raynaud's phenomenon with vasodilators such as calcium channel blockers, alpha blockers, serotonin receptor antagonists, angiotensin II receptor inhibitors, statins, local nitrates or iloprost
- Digital ulcers with phosphodiesterase 5 inhibitors (e.g. sildenafil) or iloprost
- Prevention of new digital ulcers with bosentan
- Malnutrition, secondary to intestinal flora overgrowth with tetracycline antibiotics like tetracycline
- Alveolitis with cyclophosphamide, azathioprine with or without corticosteroids
- Pulmonary arterial hypertension with endothelin receptor antagonists, phosphodiesterase 5 inhibitors and prostanoids
- Gastrooesophageal reflux disease with antacids or prokinetics
- Renal crises with angiotensin converting enzyme inhibitors and angiotensin II receptor antagonist
Systemic disease-modifying treatment with immunosuppressants is also often also used. Immunosuppressants used in its treatment include: azathioprine, methotrexate, cyclophosphamide, mycophenolate, intravenous immunoglobulin, rituximab, sirolimus, alefacept and the tyrosine kinase inhibitors, imatinib, nilotinib and dasatinib. Experimental therapies currently under investigation include endothelin receptor antagonsits, tyrosine kinase inhibitors, beta-glycan peptides, halofuginone, basiliximab, alemtuzumab, abatacept and haematopoietic stem cell transplantation.
|Immunomodulatory agents in the treatment of scleroderma|
|INN||Mechanism of action||Route of administration||Pregnancy category||Major toxicities|
|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 5-year survival rate for scleroderma is about 85%, whereas the 10-year survival rate is less than 70%. This varies according to the subtype; for instance, persons with limited skin disease have a 10-year survival rate of 71%, whereas those with diffuse skin disease have a 10-year survival rate of just 21%. The major causes of death in persons with scleroderma are: pulmonary hypertension, pulmonary fibrosis and scleroderma renal crisis. People with scleroderma are also at a heightened risk for contracting cancers (especially liver, lung, haematologic and bladder cancers) and, perhaps, cardiovascular disease.
This disease is found worldwide and women are four to nine times more likely to develop scleroderma than men. In the United States, prevalence is estimated at 240 per million and the annual incidence of scleroderma is 19 per one million. Likewise in the US it is slightly more common in African Americans than in their white counterparts. In Germany, on the other hand, the prevalence is 1-15/100,000 and the annual incidence is 0.3-2.8/100,000. In South Australia the annual incidence is 22.8 per 1 million and the prevalence 233 per 1 million. It most commonly first presents between the ages of 20 and 50 years, although any age group can be affected and is less common in the Asian population.
Scleroderma in pregnancy is a complex situation; it increases the risk to both mother and child. Overall scleroderma is associated with reduced fetal weight for gestational age. 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. In these cases hydroxychloroquine and low-dose corticosteroids might be used for disease control.
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