The cause is unknown, but it may be due to an abnormal immune response.[2] Risk factors include family history, certaingenetic factors, and exposure tosilica.[3][4][5] The underlying mechanism involves the abnormal growth ofconnective tissue, which is believed to be the result of the immune system attacking healthy tissues.[6] Diagnosis is based on symptoms, supported by askin biopsy or blood tests.[6]
While no cure is known, treatment may improve symptoms.[2] Medications used includecorticosteroids,methotrexate, andnon-steroidal anti-inflammatory drugs (NSAIDs).[2] Outcome depends on the extent of disease.[3] Those with localized disease generally have a normallife 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 theGreekskleros meaning "hard" andderma meaning "skin".[11][12]
It begins with an inciting event at the level of thevasculature, probably theendothelium. The inciting event is yet to be elucidated, but may be a viral agent,oxidative stress, or autoimmune.Endothelial cell damage andapoptosis ensue, leading to the vascular leakiness that manifests in early clinical stages as tissueoedema. At this stage, it is predominantly aTh1- andTh17-mediated disease.
After this, the vasculature is further compromised by impairedangiogenesis and impairedvasculogenesis (fewer endothelial progenitor cells), likely related to the presence of antiendothelinal cell antibodies (AECA). Despite this impairedangiogenesis, elevated levels of pro-angiogenic growth factors such asPDGF andVEGF is often seen in persons with the condition. The balance ofvasodilation and vasoconstriction becomes askew, and the net result is vasoconstriction. The damaged endothelium then serves as a point of origin for blood-clot formation and further contributes toischaemia-reperfusion injury and the generation ofreactive oxygen species. These later stages are characterised byTh2 polarity.
Fibroblasts are recruited and activated by multiplecytokines and growth factors to generatemyofibroblasts. Dysregulatedtransforming 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 increaseextracellular matrix production.Endothelin signalling is implicated in the pathophysiology of fibrosis.[26]
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.[27]
Typical scleroderma is classically defined as symmetrical skin thickening, with about 70% of cases also presenting with Raynaud's phenomenon, nail-fold capillary changes, andantinuclear 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.[28]
Laboratory testing can showantitopoisomerase antibodies, likeanti-scl70 (causing a diffuse systemic form), oranticentromere antibodies (causing a limited systemic form and the CREST syndrome). Other autoantibodies can be seen, such as anti-U3 or anti-RNA polymerase.[29]Antidouble-stranded DNA autoantibodies are likely to be present in serum.[citation needed]
Diseases that are often in the differential include:[30]
Eosinophilia is a condition in which too manyeosinophils (a type of immune cell that attacks parasites and is involved in certain allergic reactions) are present in the blood.
Eosinophilic fasciitis affects the connective tissue surrounding skeletal muscles, bones, blood vessels, and nerves in the arms and legs.
Graft-versus-host disease is an autoimmune condition that occurs as a result of bone-marrow transplants in which the immune cells from the transplanted bone marrow attack the host's body.
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:[31]
As of 2012[update], the five-year survival rate for systemic scleroderma was about 85%, whereas the 10-year survival rate was just under 70%.[44] 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.[29] People with scleroderma are also at a heightened risk for developing osteoporosis and for contracting cancer (especially liver, lung, haematologic, and bladder cancers).[45] Scleroderma is also associated with an increased risk of cardiovascular disease.[46]
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 (the average Australian life expectancy increased from 76 to 82 years in the same period).[47]
Scleroderma most commonly first presents between the ages of 20 and 50 years, although any age group can be affected.[13][29] Women are four to nine times more likely to develop scleroderma than men.[29]
This disease is found worldwide.[29] In the United States, prevalence is estimated at 240 per million and the annual incidence of scleroderma is 19 per million people.[29] Likewise in the United States, it is slightly more common inAfrican 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.[29] InGermany, the prevalence is between 10 and 150 per million people, and the annual incidence is between three and 28 per million people.[44] InSouth Australia, the annual incidence is 23 per million people, and the prevalence 233 per million people.[48]
Scleroderma in pregnancy is a complex situation; it increases the risk to both mother and child.[49] Overall, scleroderma is associated with reduced fetal weight for gestational age.[49] The treatment for scleroderma often includes known teratogens such as cyclophosphamide, methotrexate,mycophenolate, etc., so careful avoidance of such drugs during pregnancy is advised.[49] In these caseshydroxychloroquine and low-dosecorticosteroids might be used for disease control.[49]
^abcHajj-ali, RA (June 2013)."Systemic Sclerosis".Merck Manual Professional. Merck Sharp & Dohme Corp.Archived from the original on 6 March 2014. Retrieved5 March 2014.
^Jimenez, SA, Cronin, PM, Koenig, AS, O'Brien, MS, Castro, SV (15 February 2012). Varga, J, Talavera, F, Goldberg, E, Mechaber, AJ, Diamond, HS (eds.)."Scleroderma Clinical Presentation".Medscape Reference. WebMD.Archived from the original on 6 March 2014. Retrieved5 March 2014.
^Longo D, Fauci A, Kasper D, Hauser S, Jameson J, Loscalzo J (2011).Harrison's Principles of Internal Medicine (18th ed.). New York: McGraw-Hill Professional.ISBN978-0-07174889-6.[page needed]
^Marie I, Ducrotte P, Antonietti M, Herve S, Levesque H (2008). "Watermelon stomach in systemic sclerosis: its incidence and management".Alimentary Pharmacology & Therapeutics.28 (4):412–421.doi:10.1111/j.1365-2036.2008.03739.x.PMID18498445.S2CID205244678.
^abcdBalbir-Gurman A, Braun-Moscovici Y (February 2012). "Scleroderma – new aspects in pathogenesis and treatment".Best Practice & Research. Clinical Rheumatology.26 (1):13–24.doi:10.1016/j.berh.2012.01.011.PMID22424190.
^Marie I, Gehanno JF, Bubenheim M, Duval-Modeste AB, Joly P, Dominique S, et al. (February 2014). "Prospective study to evaluate the association between systemic sclerosis and occupational exposure and review of the literature".Autoimmunity Reviews.13 (2):151–56.doi:10.1016/j.autrev.2013.10.002.PMID24129037.
^Liakouli V, Cipriani P, Marrelli A, Alvaro S, Ruscitti P, Giacomelli R (August 2011). "Angiogenic cytokines and growth factors in systemic sclerosis".Autoimmunity Reviews.10 (10):590–94.doi:10.1016/j.autrev.2011.04.019.PMID21549861.
^Cipriani P, Marrelli A, Liakouli V, Di Benedetto P, Giacomelli R (August 2011). "Cellular players in angiogenesis during the course of systemic sclerosis".Autoimmunity Reviews.10 (10):641–46.doi:10.1016/j.autrev.2011.04.016.PMID21549220.
^Bosello S, De Luca G, Tolusso B, Lama G, Angelucci C, Sica G, et al. (August 2011). "B cells in systemic sclerosis: a possible target for therapy".Autoimmunity Reviews.10 (10):624–30.doi:10.1016/j.autrev.2011.04.013.PMID21545850.
^Leask A (June 2011). "The role of endothelin-1 signaling in the fibrosis observed in systemic sclerosis".Pharmacological Research.63 (6):502–03.doi:10.1016/j.phrs.2011.01.011.PMID21315153.
^Arnson Y, Amital H, Agmon-Levin N, Alon D, Sánchez-Castañón M, López-Hoyos M, et al. (June 2011). "Serum 25-OH vitamin D concentrations are linked with various clinical aspects in patients with systemic sclerosis: a retrospective cohort study and review of the literature".Autoimmunity Reviews.10 (8):490–94.doi:10.1016/j.autrev.2011.02.002.PMID21320645.
^Jimenez, SA, Cronin, PM, Koenig, AS, O'Brien, MS, Castro, SV (15 February 2012). Varga, J, Talavera, F, Goldberg, E, Mechaber, AJ, Diamond, HS (eds.)."Scleroderma Workup".Medscape Reference. WebMD.Archived from the original on 6 March 2014. Retrieved6 March 2014.
^abcdefgJimenez, SA, Cronin, PM, Koenig, AS, O'Brien, MS, Castro, SV (15 February 2012). Varga, J, Talavera, F, Goldberg, E, Mechaber, AJ, Diamond, HS (eds.)."Scleroderma".Medscape Reference. WebMD.Archived from the original on 6 March 2014. Retrieved5 March 2014.
^Jimenez, SA, Cronin, PM, Koenig, AS, O'Brien, MS, Castro, SV (15 February 2012). Varga, J, Talavera, F, Goldberg, E, Mechaber, AJ, Diamond, HS (eds.)."Scleroderma Differential Diagnoses".Medscape Reference. WebMD.Archived from the original on 6 March 2014. Retrieved6 March 2014.
^abWalker KM, Pope J (August 2012). "Treatment of systemic sclerosis complications: what to use when first-line treatment fails--a consensus of systemic sclerosis experts".Seminars in Arthritis and Rheumatism.42 (1):42–55.doi:10.1016/j.semarthrit.2012.01.003.PMID22464314.
^abFett N (July–August 2013). "Scleroderma: nomenclature, etiology, pathogenesis, prognosis, and treatments: facts and controversies".Clinics in Dermatology.31 (4):432–37.doi:10.1016/j.clindermatol.2013.01.010.PMID23806160.
^abBeyer C, Dees C, Distler JH (January 2013). "Morphogen pathways as molecular targets for the treatment of fibrosis in systemic sclerosis".Archives of Dermatological Research.305 (1):1–8.doi:10.1007/s00403-012-1304-7.PMID23208311.S2CID25073736.
^abcdRossi, S, ed. (2013).Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust.ISBN978-0-9805790-9-3.[page needed]
^Brunton, L, Chabner, B, Knollman, B (2010).Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional.ISBN978-0-07-162442-8.[page needed]
^Kennedy N, Walker J, Hakendorf P, Roberts-Thomson P (23 March 2018). "Improving life expectancy of patients with scleroderma: results from the South Australian Scleroderma Register".Internal Medicine Journal.48 (8):951–56.doi:10.1111/imj.13799.PMID29573101.S2CID4230441.
^Nikpour M, Stevens WM, Herrick AL, Proudman SM (December 2010). "Epidemiology of systemic sclerosis".Best Practice & Research. Clinical Rheumatology.24 (6):857–69.doi:10.1016/j.berh.2010.10.007.PMID21665131.
