This article is about the disease. For the mushroom, see Scleroderma (fungus).
Not to be confused with scleredema.

Classification and external resources
Specialty Rheumatology
ICD-10 L94.0-L94.1, M34
ICD-9-CM 701.0 710.1
MedlinePlus 000429

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]


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]


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]

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]


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]


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


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]


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.


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]


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]


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


  1. 1 2 3 4 5 6 7 8 9 10 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". Medscape Reference. WebMD. Retrieved 5 March 2014.
  2. 1 2 3 4 Hajj-ali, RA (June 2013). "Systemic Sclerosis". Merck Manual Professional. Merck Sharp & Dohme Corp. Retrieved 5 March 2014.
  3. 1 2 3 4 5 Balbir-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. PMID 22424190.
  4. 1 2 3 Greenblatt MB, Aliprantis AO (January 2013). "The immune pathogenesis of scleroderma: context is everything." (PDF). Current Rheumatology Reports. 15 (1): 297. doi:10.1007/s11926-012-0297-8. PMC 3539168Freely accessible. PMID 23288576.
  5. 1 2 3 Barnes J, Mayes MD (March 2012). "Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers.". Current Opinion in Rheumatology. 24 (2): 165–70. doi:10.1097/BOR.0b013e32834ff2e8. PMID 22269658.
  6. 1 2 3 Dospinescu P, Jones GT, Basu N (March 2013). "Environmental risk factors in systemic sclerosis.". Current opinion in rheumatology. 25 (2): 179–83. doi:10.1097/BOR.0b013e32835cfc2d. PMID 23287382.
  7. 1 2 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. Retrieved 5 March 2014.
  8. Gabrielli A, Avvedimento EV, Krieg T (2009). "Scleroderma". New England Journal of Medicine. 360 (19): 1989–2003. doi:10.1056/NEJMra0806188. PMID 19420368.
  9. Klippel, John H. Primer On the Rheumatic Diseases 11ED. Atlanta, GA: Arthritis Foundation. ISBN 1-912423-16-2.
  10. 1 2 Longo, D; Fauci, A; Kasper, D; Hauser, S; Jameson, J; Loscalzo, J (2011). Harrison's Principles of Internal Medicine (18 ed.). New York: McGraw-Hill Professional. ISBN 978-0-07174889-6.
  12. Marie I, Gehanno JF, Bubenheim M, Duval-Modeste AB, Joly P, Dominique S, Bravard P, Noël D, Cailleux AF, Weber J, Lagoutte P, Benichou J, Levesque H (February 2014). "Prospective study to evaluate the association between systemic sclerosis and occupational exposure and review of the literature.". Autoimmunity Reviews. 13 (2): 151–6. doi:10.1016/j.autrev.2013.10.002. PMID 24129037.
  13. Valančienė G, Jasaitienė D, Valiukevičienė S (2010). "Pathogenesis and treatment modalities of localized scleroderma." (PDF). Medicina. 46 (10): 649–56. PMID 21393982.
  14. Katsumoto TR, Whitfield ML, Connolly MK (2011). "The pathogenesis of systemic sclerosis.". Annual Review of Pathology. 6: 509–37. doi:10.1146/annurev-pathol-011110-130312. PMID 21090968.
  15. 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): 590–4. doi:10.1016/j.autrev.2011.04.019. PMID 21549861.
  16. 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): 641–6. doi:10.1016/j.autrev.2011.04.016. PMID 21549220.
  17. Bosello S, De Luca G, Tolusso B, Lama G, Angelucci C, Sica G, Ferraccioli G (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. PMID 21545850.
  18. Hunzelmann N, Krieg T (May 2010). "Scleroderma: from pathophysiology to novel therapeutic approaches." (PDF). Experimental Dermatology. 19 (5): 393–400. doi:10.1111/j.1600-0625.2010.01082.x. PMID 20507361.
  19. Leask A (June 2011). "The role of endothelin-1 signaling in the fibrosis observed in systemic sclerosis.". Pharmacological research. 63 (6): 502–3. doi:10.1016/j.phrs.2011.01.011. PMID 21315153.
  20. Arnson Y, Amital H, Agmon-Levin N, Alon D, Sánchez-Castañón M, López-Hoyos M, Matucci-Cerinic M, Szücs G, Shapira Y, Szekanecz Z, Shoenfeld Y (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): 490–4. doi:10.1016/j.autrev.2011.02.002. PMID 21320645.
  21. 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. Retrieved 6 March 2014.
  22. 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. Retrieved 6 March 2014.
  23. Elston, William D. James, Timothy G. Berger, Dirk M. (2006). Andrew's diseases of the skin: clinical dermatology (10 ed.). Philadelphia, PA: Saunders Elsevier. pp. 169–172. ISBN 978-0808923510.
  24. 1 2 Walker 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. PMID 22464314.
  25. 1 2 Fett N (July–August 2013). "Scleroderma: nomenclature, etiology, pathogenesis, prognosis, and treatments: facts and controversies.". Clinics in dermatology. 31 (4): 432–7. doi:10.1016/j.clindermatol.2013.01.010. PMID 23806160.
  26. 1 2 Shah AA, Wigley FM (April 2013). "My approach to the treatment of scleroderma.". Mayo Clinic Proceedings. 88 (4): 377–93. doi:10.1016/j.mayocp.2013.01.018. PMC 3666163Freely accessible. PMID 23541012.
  27. 1 2 Kowal-Bielecka O, Bielecki M, Kowal K (2013). "Recent advances in the diagnosis and treatment of systemic sclerosis." (PDF). Polskie Archiwum Medycyny Wewnetrznej. 123 (1-2): 51–8. PMID 23344666.
  28. 1 2 Beyer 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. PMID 23208311.
  29. 1 2 Leask A (June 2012). "Emerging targets for the treatment of scleroderma.". Expert Opinion on Emerging Drugs. 17 (2): 173–9. doi:10.1517/14728214.2012.678833. PMID 22533795.
  30. Manno R, Boin F (November 2010). "Immunotherapy of systemic sclerosis." (PDF). Immunotherapy. 2 (6): 863–78. doi:10.2217/imt.10.69. PMC 3059511Freely accessible. PMID 21091117.
  31. Postlethwaite AE, Harris LJ, Raza SH, Kodura S, Akhigbe T (April 2010). "Pharmacotherapy of systemic sclerosis." (PDF). Expert Opinion on Pharmacotherapy. 11 (5): 789–806. doi:10.1517/14656561003592177. PMC 2837533Freely accessible. PMID 20210685.
  32. Ong VH, Denton CP (May 2010). "Innovative therapies for systemic sclerosis.". Current Opinion in Rheumatology. 22 (3): 264–72. doi:10.1097/BOR.0b013e328337c3d6. PMID 20190640.
  33. 1 2 3 4 Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  34. Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
  35. "Medscape Multispecialty – Home page". WebMD. Retrieved 27 November 2013.
  36. 1 2 Sticherling M (October 2012). "Systemic sclerosis-dermatological aspects. Part 1: Pathogenesis, epidemiology, clinical findings.". Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 10 (10): 705–18; quiz 716. doi:10.1111/j.1610-0387.2012.07999.x. PMID 22913330.
  37. "Scleroderma Prognosis - Scleroderma Health Information - NY Times Health". Retrieved 2015-09-12.
  38. Ngian GS, Sahhar J, Wicks IP, Van Doornum S (August 2011). "Cardiovascular disease in systemic sclerosis--an emerging association?" (PDF). Arthritis Research & Therapy. 13 (4): 237. doi:10.1186/ar3445. PMC 3239376Freely accessible. PMID 21888685.
  39. Szekanecz É, Szamosi S, Horváth Á, Németh Á, Juhász B, Szántó J, Szücs G, Szekanecz Z (October 2012). "Malignancies associated with systemic sclerosis.". Autoimmunity Reviews. 11 (12): 852–5. doi:10.1016/j.autrev.2012.02.021. PMID 22410174.
  40. Shah AA, Rosen A (November 2011). "Cancer and systemic sclerosis: novel insights into pathogenesis and clinical implications." (PDF). Current Opinion in Rheumatology. 23 (6): 530–5. doi:10.1097/BOR.0b013e32834a5081. PMC 3373179Freely accessible. PMID 21825998.
  41. Onishi A, Sugiyama D, Kumagai S, Morinobu A (July 2013). "Cancer incidence in systemic sclerosis: meta-analysis of population-based cohort studies.". Arthritis and Rheumatism. 65 (7): 1913–21. doi:10.1002/art.37969. PMID 23576072.
  42. Bonifazi M, Tramacere I, Pomponio G, Gabrielli B, Avvedimento EV, La Vecchia C, Negri E, Gabrielli A (22 November 2012). "Systemic sclerosis (scleroderma) and cancer risk: systematic review and meta-analysis of observational studies" (PDF). Rheumatology. 52 (1): 143–154. doi:10.1093/rheumatology/kes303. PMID 23175568.
  43. 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. PMID 21665131.
  44. Gelber AC, Manno RL, Shah AA, Woods A, Le EN, Boin F, Hummers LK, Wigley FM (July 2013). "Race and association with disease manifestations and mortality in scleroderma: a 20-year experience at the Johns Hopkins Scleroderma Center and review of the literature.". Medicine. 92 (4): 191–205. doi:10.1097/MD.0b013e31829be125. PMID 23793108.
  45. 1 2 3 4 Lidar M, Langevitz P (May 2012). "Pregnancy issues in scleroderma.". Autoimmunity Reviews. 11 (6-7): A515–9. doi:10.1016/j.autrev.2011.11.021. PMID 22155199.

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