Wikipedia

Scleroderma

This article is about the disease. For the mushroom, seeScleroderma (fungus).
Not to be confused withscleredema.

Sclerodermais a group ofautoimmune diseasesthat may result in changes to theskin,blood vessels,muscles,andinternal 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 asCREST syndrome,classically results incalcium deposits,Raynaud's syndrome,esophagealproblems,thickening of the skin of the fingers and toes,andareas of small, dilated blood vessels.[1]

Scleroderma
A type of localized scleroderma known asmorphea
SpecialtyRheumatology
Usual onsetMiddle age[1]
TypesLocalized,systemic scleroderma[2]
CausesUnknown[2]
Risk factorsFamily history, certaingeneticfactors, exposure tosilica[3][4][5]
Diagnostic methodBased on symptoms,skin biopsy,blood tests[6]
Differential diagnosisMixed connective tissue disease,systemic lupus erythematosus,polymyositis,dermatomyositis[1]
TreatmentSupportive care[1]
MedicationCorticosteroids,methotrexate,non-steroidal anti-inflammatory drugs(NSAIDs)[2]
PrognosisLocalized:Normal life expectancy[7]
Systemic:Decreased life expectancy[3]
Frequency3 per 100,000 per year (systemic)[3]

The cause is unknown, but it may be due to an abnormal immune response.[2]Risk factors include family history, certaingeneticfactors, 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 biopsyor 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 theGreeksklerosmeaning "hard" anddermameaning "skin".[11][12]

Signs and symptoms

edit
Arm of a person with scleroderma showing skin lesions
Dark, shiny skin on distal phalanges of both hands in systemic sclerosis

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

Cause

edit

Scleroderma is caused by genetic and environmental factors.[4][5][16][17]Mutations inHLAgenes seem to play a crucial role in thepathogenesisof some cases; likewisesilica,aromaticandchlorinatedsolvents,ketones,trichloroethylene,weldingfumes, andwhite spiritsexposure seems to contribute to the condition in a small proportion of affected persons.[4][5][16][17][18]

Pathophysiology

edit

Scleroderma is characterised by increasedsynthesisofcollagen(leading to thesclerosis), damage to small blood vessels, activation ofT lymphocytes,and production of alteredconnective tissue.[19]Its proposed pathogenesis is the following:[20][21][22][23][24]

  • 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 celldamage andapoptosisensue, 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 impairedangiogenesisand 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 asPDGFandVEGFis often seen in persons with the condition. The balance ofvasodilationand 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 injuryand the generation ofreactive oxygen species.These later stages are characterised byTh2polarity.
  • The damaged endothelium upregulatesadhesion moleculesandchemokinesto attractleucocytes,which enables the development of innate and adaptive immune responses, including loss of tolerance to various oxidisedantigens,which includestopoisomerase I.B cellsmature intoplasma cells,which furthers the autoimmune component of the condition. T cells differentiate into subsets, including Th2 cells, which play a vital role in tissuefibrosis.Anti–topoisomerase 1antibodies,in turn, stimulatetype I interferonproduction.
  • Fibroblastsare recruited and activated by multiplecytokinesand 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-6and TGF-β produced by the B cells decrease collagen degradation and increaseextracellular matrixproduction.Endothelin signallingis implicated in the pathophysiology of fibrosis.[25]

Vitamin Dis 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

edit

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.[27]

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.[28] Antidouble-stranded DNA autoantibodies are likely to be present in serum.[citation needed]

Differential

edit

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

Classification

edit

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

edit

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

Systemicdisease-modifying treatmentwith immunosuppressants is often used.[16][32][33][34][35][36]Immunosuppressants used in its treatment includeazathioprine,methotrexate,cyclophosphamide,mycophenolate,intravenousimmunoglobulin,rituximab,sirolimus,alefacept,and the tyrosine kinase inhibitors,imatinib,nilotinib,anddasatinib.[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,andhaematopoietic 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 ofhuman 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 tomercaptopurine PO, IV D (Au) Myelosuppressionandrarelymalignancy, hepatitis, infection,hepatic sinusoidal obstruction syndromeand 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 cystitisandrarelyheart failure, pulmonary fibrosis,hepatic sinusoidal obstruction syndrome,malignancy andSIADH
Dasatinib Tyrosine kinaseinhibitor against various proangiogenic growth factors (including PDGF and VEGF). PO D (Au) Fluid retention, myelosuppression, haemorrhage, infections, pulmonary hypertension, electrolyte anomalies anduncommonlyhepatotoxicity, heart dysfunction/failure, myocardial infarction, QT interval prolongation, renal failure and hypersensitivity.
Imatinib As above PO D (Au) As above andrarely:GI perforation, avascular necrosis andrhabdomyolysis
Immunoglobulin Immunoglobulin, modulates the immune system. IV N/A Varies
Methotrexate Antifolate; inhibitsdihydrofolate reductase. PO, IV, IM, SC, IT D (Au) Myeosuppression, pulmonary toxicity, hepatotoxicity, neurotoxicity andrarelykidney failure, hypersensitivity reactions, skin and bone necrosis, and osteoporosis
Mycophenolate Inosine monophosphate dehydrogenaseinhibitor, leading to reduced purine biosynthesis in lymphocytes. PO, IV D (Au) Myelosuppression, blood clots,less commonlyGI perforation/haemorrhage andrarelypancreatitis,hepatitis,aplastic anaemiaandpure red cell aplasia.
Nilotinib As per dasatinib PO D (Au) As per imatinib
Rituximab Monoclonal antibody againstCD20,which is expressed on B lymphocytes IV C (Au) Infusion-related reactions, infection,neutropenia,reduced immunoglobulin levels, arrhythmias,less commonlyanaemia, thrombocytopenia, angina, myocardial infarction, heart failure, andrarelyhaemolytic anaemia,aplastic anaemia,serum sickness, severe skin conditions, pulmonary infiltrates,pneumonitis,cranial neuropathy (vision or hearing loss) andprogressive multifocal leucoencephalopathy.
Sirolimus mTORinhibitor, thereby reducing cytokine-induced lymphocyte proliferation. PO C (Au) Neutropenia,hypokalaemia,interstitial lung disease,pericardial effusion,pleural effusion,less commonlypulmonary haemorrhage, nephrotic syndrome, andrarelyhepatotoxicity andlymphoedema.
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

edit

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 (the average Australian life expectancy increased from 76 to 82 years in the same period).[46]

Epidemiology

edit

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 inAfrican Americansthan 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]InGermany,the prevalence is between 10 and 150 per million people, and the annual incidence is between three and 28 per million people.[43]InSouth Australia,the annual incidence is 23 per million people, and the prevalence 233 per million people.[47]

Pregnancy

edit

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 caseshydroxychloroquineand low-dosecorticosteroidsmight be used for disease control.[48]

See also

edit

References

edit
  1. ^abcdefg"Scleroderma".NORD (National Organization for Rare Disorders).2007.Archivedfrom the original on 8 September 2016.Retrieved14 July2017.
  2. ^abcdefgh"Scleroderma".GARD.2017.Archivedfrom the original on 25 January 2017.Retrieved14 July2017.
  3. ^abcdefghJameson L (2018). "Chapter 353".Harrison's Principles of Internal Medicine(20th ed.). McGraw Hill.
  4. ^abcdBarnes 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.PMID22269658.S2CID24050211.
  5. ^abcdGreenblatt MB, Aliprantis AO (January 2013)."The immune pathogenesis of scleroderma: context is everything".Current Rheumatology Reports.15(1): 297.doi:10.1007/s11926-012-0297-8.PMC3539168.PMID23288576.
  6. ^abcd"Handout on Health: Scleroderma".NIAMS.August 2016.Archivedfrom the original on 4 July 2017.Retrieved15 July2017.
  7. ^abUnsal E (2006).Current Opinions in Pediatric Rheumatology.Nova Publishers. p. 302.ISBN9781594548710.Archivedfrom the original on 2017-09-06.
  8. ^Denton CP, Khanna D (October 2017). "Systemic sclerosis".Lancet.390(10103): 1685–1699.doi:10.1016/s0140-6736(17)30933-9.PMID28413064.S2CID22247432.
  9. ^Mackay IR, Rose NR (2006).The Autoimmune Diseases.Academic Press. p. 369.ISBN9780080454740.
  10. ^Firestein GS, Kelley WN, Budd RC (2012).Kelley's Textbook of Rheumatology.Elsevier Health Sciences. p. 1366.ISBN978-1437717389.Archivedfrom the original on 2017-08-04.
  11. ^Harper D."scleroderma".Online Etymology Dictionary.
  12. ^σκληρός,δέρμα.Liddell, Henry George;Scott, Robert;A Greek–English Lexiconat thePerseus Project.
  13. ^abcHajj-ali, RA (June 2013)."Systemic Sclerosis".Merck Manual Professional.Merck Sharp & Dohme Corp.Archivedfrom the original on 6 March 2014.Retrieved5 March2014.
  14. ^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.Archivedfrom the original on 6 March 2014.Retrieved5 March2014.
  15. ^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]
  16. ^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.
  17. ^abDospinescu 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.PMID23287382.S2CID37543720.
  18. ^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.
  19. ^Valančienė G, Jasaitienė D, Valiukevičienė S (2010)."Pathogenesis and treatment modalities of localized scleroderma"(PDF).Medicina.46(10): 649–56.doi:10.3390/medicina46100092.PMID21393982.Archived(PDF)from the original on 2014-03-06.
  20. ^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.PMID21090968.
  21. ^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.
  22. ^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.
  23. ^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.
  24. ^Hunzelmann N, Krieg T (May 2010). "Scleroderma: from pathophysiology to novel therapeutic approaches".Experimental Dermatology.19(5): 393–400.doi:10.1111/j.1600-0625.2010.01082.x.PMID20507361.S2CID40400573.
  25. ^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.
  26. ^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.
  27. ^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.Archivedfrom the original on 6 March 2014.Retrieved6 March2014.
  28. ^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.Archivedfrom the original on 6 March 2014.Retrieved5 March2014.
  29. ^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.Archivedfrom the original on 6 March 2014.Retrieved6 March2014.
  30. ^Elston W, James WD, Berger TG, Dirk M (2006).Andrew's diseases of the skin: clinical dermatology(10 ed.). Philadelphia, PA: Saunders Elsevier. pp.169–172.ISBN978-0808923510.
  31. ^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.
  32. ^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.
  33. ^abShah 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.PMC3666163.PMID23541012.
  34. ^abKowal-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): 51–58.PMID23344666.Archived(PDF)from the original on 2014-03-06.
  35. ^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.
  36. ^abLeask A (June 2012). "Emerging targets for the treatment of scleroderma".Expert Opinion on Emerging Drugs.17(2): 173–79.doi:10.1517/14728214.2012.678833.PMID22533795.S2CID29026417.
  37. ^Manno R, Boin F (November 2010)."Immunotherapy of systemic sclerosis".Immunotherapy.2(6): 863–78.doi:10.2217/imt.10.69.PMC3059511.PMID21091117.
  38. ^Postlethwaite AE, Harris LJ, Raza SH, Kodura S, Akhigbe T (April 2010)."Pharmacotherapy of systemic sclerosis".Expert Opinion on Pharmacotherapy.11(5): 789–806.doi:10.1517/14656561003592177.PMC2837533.PMID20210685.
  39. ^Ong VH, Denton CP (May 2010). "Innovative therapies for systemic sclerosis".Current Opinion in Rheumatology.22(3): 264–72.doi:10.1097/BOR.0b013e328337c3d6.PMID20190640.S2CID24631979.
  40. ^abcdRossi, S, ed. (2013).Australian Medicines Handbook(2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust.ISBN978-0-9805790-9-3.[page needed]
  41. ^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]
  42. ^"Medscape Multispecialty – Home page".WebMD.Archivedfrom the original on 13 November 2013.Retrieved27 November2013.[full citation needed]
  43. ^abSticherling M (October 2012)."Systemic sclerosis-dermatological aspects. Part 1: Pathogenesis, epidemiology, clinical findings".Journal der Deutschen Dermatologischen Gesellschaft.10(10): 705–18, quiz 716.doi:10.1111/j.1610-0387.2012.07999.x.PMID22913330.S2CID7422759.
  44. ^Calderon LM, Domsic RT, Shah AA, Pope JE (May 2023)."Preventative Care in Scleroderma: What Is the Best Approach to Bone Health and Cancer Screening?".Rheumatic Disease Clinics of North America.49(2): 411–423.doi:10.1016/j.rdc.2023.01.011.PMC10845237.PMID37028844.
  45. ^Cen X, Feng S, Wei S, Yan L, Sun L (November 2020)."Systemic sclerosis and risk of cardiovascular disease: A PRISMA-compliant systemic review and meta-analysis of cohort studies".Medicine.99(47): e23009.doi:10.1097/MD.0000000000023009.PMC7676589.PMID33217802.
  46. ^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.
  47. ^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.
  48. ^abcdLidar M, Langevitz P (May 2012). "Pregnancy issues in scleroderma".Autoimmunity Reviews.11(6–7): A515–19.doi:10.1016/j.autrev.2011.11.021.PMID22155199.
edit
Retrieved from "https://en.wikipedia.org/w/index.php?title=Scleroderma&oldid=1242962707"