Sections

Scleroderma

Medication

Medication Summary

Pharmacologic therapy consists principally of treatment directed toward complications of the disease and providing symptomatic relief. Nintedanib and tocilizumab are approved by the US Food and Drug Administration to slow the rate of decline in pulmonary function in adults with interstitial lung disease associated with scleroderma.

Class Summary

These agents are used to treat inflammatory complications (eg, myositis, pneumonitis).

Prednisone (Deltasone, Rayos, Prednisone Intensol, Sterapred, Sterapred DS)

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Prednisone is an immunosuppresant used for treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing inflammatory cell activity. Prednisone is inactive and must be metabolized to prednisolone. Metabolism may be impaired in patients with liver disease. High dose corticosteroids (e.g.- prednisone >20mg) should be avoided in systemic sclerosis because it increases the risk of renal crisis.

Class Summary

These agents inhibit key steps in immune reactions.

Azathioprine (Azasan, Imuran)

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Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA and RNA. It may decrease proliferation of immune cells, which results in lower autoimmune activity.

Methotrexate (Trexall, Rheumatrex, Otrexup, Rasuvo)

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Methotrexate is an antimetabolite that inhibits DNA synthesis and cell division in malignant cells. It may suppress the immune system. Methotrexate use in systemic sclerosis should be avoided in severe or active interstitial lung disease.

Cyclophosphamide (Cytoxan)

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Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth and proliferation of normal and neoplastic cells.

Mycophenolate (CellCept, Myfortic, MMF)

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Mycophenolate is a potent selective, noncompetitive, and reversible inhibitor of purine synthesis. It has cytostatic effects on lymphocytes. It may suppress the immune system.

Rituximab (Rituxan)

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Rituximab is a potent immunosuppressive drug that acts by causing a selective depletion of B lymphocytes. Rituximab was initially approved for treatment of certain hematologic malignancies. However, owing to its potent immunosuppressive effects, its use in the therapy of autoimmune diseases, including systemic sclerosis, is expanding rapidly.

Tocilizumab (Actemra)

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Tocilizumab is indicated for treatment of interstitial lung disease in systemic sclerosis that is refractory or highly progressive.

Class Summary

Nintedanib is a tyrosine kinase inhibitor that targets growth factors (eg, vascular endothelial growth factor receptor [VEGFR], fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor [PDGFR] 1-3, colony-stimulating factor 1 receptor [CSFIR]) that are implicated in the pathogenesis of interstitial lung diseases.

Nintedanib (Ofev)

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Indicated to slow the rate of decline in pulmonary function in patients who have interstitial lung disease associated with scleroderma.

Class Summary

These agents bind to endothelin receptors present in endothelium and vascular smooth muscle cells. The effect can result in vasodilation.

Bosentan (Tracleer)

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Bosentan is a dual endothelin A and B receptor antagonist for treatment of pulmonary arterial hypertension. It decreases both pulmonary and systemic vascular resistance and increases cardiac output without increasing heart rate

Ambrisentan (Letairis)

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Ambrisentan is an endothelin receptor antagonist indicated for pulmonary arterial hypertension in patients with World Health Organization (WHO) class II or III symptoms. It improves exercise ability and decreases progression of clinical symptoms. Ambrisentan inhibits vessel constriction and elevation of blood pressure by competitively binding to endothelin-1 receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to significant increase in cardiac index associated with significant reduction in pulmonary artery pressure, pulmonary vascular resistance, and mean right atrial pressure.

Because of the risks of hepatic injury and teratogenic potential, this agent is available only through the Letairis Education and Access Program (LEAP). Prescribers and pharmacies must register with LEAP in order to prescribe and dispense. For more information, see http://www.letairis.com or call (866) 664-LEAP (5327).

Macitentan (Opsumit)

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Macitentan is a novel agent acting as dual endothelin receptor-1(ETA and ETB) antagonist with sustained receptor-binding properties. It has been approved by the FDA for the treatment of pulmonary hypertension. Studies assessing its efficacy and safety in ischemic digital ulcers secondary to Raynaud phenomenon is systemic sclerosis are under way.

Class Summary

These agents may increase vasodilation in the pulmonary vascular bed.

Tadalafil (Adcirca)

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Tadalafil is aphosphodiesterase type-5 inhibitor indicated for improving and increasing exercise capacity in patients with World Health Organization (WHO) class I pulmonary arterial hypertension. It increases cyclic guanosine monophosphate (cGMP), which is the final mediator in the nitric-oxide pathway. Tadalafil has been shown to improve systemic sclerosis associated pulmonary hypertension and Raynaud phenomenon. Tadalafil has an extended half-life and therefore can be administered once daily without compromising its effectiveness.

Sildenafil (Revatio)

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Sildenafil promotes selective smooth muscle relaxation in lung vasculature, possibly by inhibiting phosphodiesterase type 5. This effect results in subsequent reduction of pulmonary artery pressure and increase in cardiac output.

Sildenafil has been shown to be effective in reducing pulmonary artery pressure in systemic sclerosis associated pulmonary hypertension. Because of its potent peripheral vasculature vasodilatory effects it has also been used for treatment of severe Raynaud phenomenon with digital ulcers. However, owing to the short duration of its vasodilatory effects, sildenafil has to be administered several times per day.

Class Summary

These agents may improve the fibrotic aspects of systemic sclerosis.

Penicillamine (Cuprimine, Depen)

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Penicillamine inhibits the formation of mature collagen crosslinks, rendering un-crosslinked molecules more susceptible to proteolytic degradation. The inhibition of collagen crosslink formation very likely causes a marked decrease in tissue stiffness, an important profibrotic mechanism.

Follow-up

van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 2013 Nov. 65(11):2737-47. [QxMD MEDLINE Link].
van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013 Nov. 72(11):1747-55. [QxMD MEDLINE Link].
RODNAN GP, BENEDEK TG. An historical account of the study of progressive systemic sclerosis (diffuse scleroderma). Ann Intern Med. 1962 Aug. 57:305-19. [QxMD MEDLINE Link].
David M. A case of scleroderma mentioned by Hippocrates in his aphorisms. Korot. 1981. 8(1-2):61-3. [QxMD MEDLINE Link].
Rodnan G, Benedeck T. History of scleroderma. Ann Intern Med. 1978. 89:725.
Goetz RH. Pathology of progressive systemic sclerosis (generalized scleroderma) with special reference to changes in the viscera. Clin Proc S Afr. 1945. 4:337-342.
Katsumoto TR, Whitfield ML, Connolly MK. The pathogenesis of systemic sclerosis. Annu Rev Pathol. 2011. 6:509-37. [QxMD MEDLINE Link].
Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007 Mar. 117(3):557-67. [QxMD MEDLINE Link].
Matucci-Cerinic M, Kahaleh B, Wigley FM. Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum. 2013 Aug. 65(8):1953-62. [QxMD MEDLINE Link].
Jimenez SA. Role of Endothelial to Mesenchymal Transition in the Pathogenesis of the Vascular Alterations in Systemic Sclerosis. ISRN Rheumatol. 2013. 2013:835948. [QxMD MEDLINE Link].
Varga J, Whitfield ML. Transforming growth factor-beta in systemic sclerosis (scleroderma). Front Biosci (Schol Ed). 2009. 1:226-35. [QxMD MEDLINE Link].
Gilbane AJ, Denton CP, Holmes AM. Scleroderma pathogenesis: a pivotal role for fibroblasts as effector cells. Arthritis Res Ther. 2013. 15(3):215. [QxMD MEDLINE Link].
Gu YS, Kong J, Cheema GS, Keen CL, Wick G, Gershwin ME. The immunobiology of systemic sclerosis. Semin Arthritis Rheum. 2008 Oct. 38(2):132-60. [QxMD MEDLINE Link].
Chizzolini C, Brembilla NC, Montanari E, Truchetet ME. Fibrosis and immune dysregulation in systemic sclerosis. Autoimmun Rev. 2011 Mar. 10(5):276-81. [QxMD MEDLINE Link].
Barsotti S, Stagnaro C, d'Ascanio A, Della Rossa A. One year in review 2016: systemic sclerosis. Clin Exp Rheumatol. 2016 Sep-Oct. 34 Suppl 100 (5):3-13. [QxMD MEDLINE Link]. [Full Text].
Dospinescu P, Jones GT, Basu N. Environmental risk factors in systemic sclerosis. Curr Opin Rheumatol. 2013 Mar. 25(2):179-83. [QxMD MEDLINE Link].
Nietert PJ, Sutherland SE, Silver RM, Pandey JP, Knapp RG, Hoel DG. Is occupational organic solvent exposure a risk factor for scleroderma?. Arthritis Rheum. 1998 Jun. 41(6):1111-8. [QxMD MEDLINE Link].
Marie I, Gehanno JF, Bubenheim M, Duval-Modeste AB, Joly P, Dominique S. Prospective study to evaluate the association between systemic sclerosis and occupational exposure and review of the literature. Autoimmun Rev. 2014 Feb. 13(2):151-6. [QxMD MEDLINE Link].
Rubio-Rivas M, Moreno R, Corbella X. Occupational and environmental scleroderma. Systematic review and meta-analysis. Clin Rheumatol. 2017 Mar. 36 (3):569-582. [QxMD MEDLINE Link].
Barragán-Martínez C, Speck-Hernández CA, Montoya-Ortiz G, Mantilla RD, Anaya JM, Rojas-Villarraga A. Organic solvents as risk factor for autoimmune diseases: a systematic review and meta-analysis. PLoS One. 2012. 7(12):e51506. [QxMD MEDLINE Link]. [Full Text].
Barbosa NS, Wetter DA, Wieland CN, Shenoy NK, Markovic SN, Thanarajasingam U. Scleroderma Induced by Pembrolizumab: A Case Series. Mayo Clin Proc. 2017 Jul. 92 (7):1158-1163. [QxMD MEDLINE Link].
Moroncini G, Mori S, Tonnini C, Gabrielli A. Role of viral infections in the etiopathogenesis of systemic sclerosis. Clin Exp Rheumatol. 2013 Mar-Apr. 31(2 Suppl 76):3-7. [QxMD MEDLINE Link].
Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am. 2003 May. 29(2):239-54. [QxMD MEDLINE Link].
Chifflot H, Fautrel B, Sordet C, Chatelus E, Sibilia J. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum. 2008 Feb. 37(4):223-35. [QxMD MEDLINE Link].
Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012 Mar. 24(2):165-70. [QxMD MEDLINE Link].
Ranque B, Mouthon L. Geoepidemiology of systemic sclerosis. Autoimmun Rev. 2010 Mar. 9(5):A311-8. [QxMD MEDLINE Link].
Calderon LM, Pope JE. Scleroderma epidemiology update. Curr Opin Rheumatol. 2021 Mar 1. 33 (2):122-127. [QxMD MEDLINE Link].
Silver RM, Bogatkevich G, Tourkina E, Nietert PJ, Hoffman S. Racial differences between blacks and whites with systemic sclerosis. Curr Opin Rheumatol. 2012 Nov. 24(6):642-8. [QxMD MEDLINE Link].
Reveille JD. Ethnicity and race and systemic sclerosis: how it affects susceptibility, severity, antibody genetics, and clinical manifestations. Curr Rheumatol Rep. 2003 Apr. 5(2):160-7. [QxMD MEDLINE Link].
Gelber AC, Manno RL, Shah AA, Woods A, Le EN, Boin F, et al. 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 (Baltimore). 2013 Jul. 92(4):191-205. [QxMD MEDLINE Link].
Laing TJ, Gillespie BW, Toth MB, Mayes MD, Gallavan RH Jr, Burns CJ. Racial differences in scleroderma among women in Michigan. Arthritis Rheum. 1997 Apr. 40(4):734-42. [QxMD MEDLINE Link].
Arnett FC, Howard RF, Tan F, Moulds JM, Bias WB, Durban E, et al. Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype. Arthritis Rheum. 1996 Aug. 39(8):1362-70. [QxMD MEDLINE Link].
De Angelis R, et al; Systemic sclerosis PRogression INvestiGation group (SPRING). Sex-related Differences in Systemic Sclerosis: A Multicenter Cross-sectional Study From the National Registry of the Italian Society for Rheumatology. J Rheumatol. 2022 Feb. 49 (2):176-185. [QxMD MEDLINE Link].
Frerix M, Kröger K, Szalay G, Müller-Ladner U, Tarner IH. Is osteonecrosis of the lunate bone an underestimated feature of systemic sclerosis? A case series of nine patients and review of literature. Semin Arthritis Rheum. 2015 Aug 4. [QxMD MEDLINE Link].
Heřmánková B, Špiritović M, Šmucrová H, Oreská S, Štorkánová H, Komarc M, et al. Female Sexual Dysfunction and Pelvic Floor Muscle Function Associated with Systemic Sclerosis: A Cross-Sectional Study. Int J Environ Res Public Health. 2022 Jan 5. 19 (1):[QxMD MEDLINE Link]. [Full Text].
Barnett AJ, Miller MH, Littlejohn GO. A survival study of patients with scleroderma diagnosed over 30 years (1953-1983): the value of a simple cutaneous classification in the early stages of the disease. J Rheumatol. 1988 Feb. 15(2):276-83. [QxMD MEDLINE Link].
Mayes MD, Lacey JV Jr, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003 Aug. 48(8):2246-55. [QxMD MEDLINE Link].
Elhai M, Meune C, Avouac J, Kahan A, Allanore Y. Trends in mortality in patients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford). 2012 Jun. 51(6):1017-26. [QxMD MEDLINE Link].
Nikpour M, Baron M. Mortality in systemic sclerosis: lessons learned from population-based and observational cohort studies. Curr Opin Rheumatol. 2014 Mar. 26(2):131-7. [QxMD MEDLINE Link].
Nihtyanova SI, Tang EC, Coghlan JG, Wells AU, Black CM, Denton CP. Improved survival in systemic sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort study. QJM. 2010 Feb. 103(2):109-15. [QxMD MEDLINE Link].
Cottrell TR, Wise RA, Wigley FM, Boin F. The degree of skin involvement identifies distinct lung disease outcomes and survival in systemic sclerosis. Ann Rheum Dis. 2014 Jun 1. 73(6):1060-6. [QxMD MEDLINE Link].
Winstone TA, Assayag D, Wilcox PG, Dunne JV, Hague CJ, Leipsic J. Predictors of mortality and progression in scleroderma-associated interstitial lung disease: A systematic review. Chest. 2014 Feb 27. [QxMD MEDLINE Link].
Chung L, Domsic RT, Lingala B, Alkassab F, Bolster M, Csuka ME, et al. Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry. Arthritis Care Res (Hoboken). 2014 Mar. 66(3):489-95. [QxMD MEDLINE Link].
Woodworth TG, Suliman YA, Li W, Furst DE, Clements P. Scleroderma renal crisis and renal involvement in systemic sclerosis. Nat Rev Nephrol. 2016 Nov. 12 (11):678-691. [QxMD MEDLINE Link].
Jancin B. Be vigilant for scleroderma renal crisis. Rheumatology News. Available at https://www.mdedge.com/rheumatology/article/223925/lupus-connective-tissue-diseases/be-vigilant-scleroderma-renal-crisis. June 15, 2020; Accessed: February 3 2022.
Krieg T, Takehara K. Skin disease: a cardinal feature of systemic sclerosis. Rheumatology (Oxford). 2009 Jun. 48 Suppl 3:iii14-8. [QxMD MEDLINE Link].
Czirják L, Foeldvari I, Müller-Ladner U. Skin involvement in systemic sclerosis. Rheumatology (Oxford). 2008 Oct. 47 Suppl 5:v44-5. [QxMD MEDLINE Link].
Abignano G, Del Galdo F. Quantitating skin fibrosis: innovative strategies and their clinical implications. Curr Rheumatol Rep. 2014 Mar. 16(3):404. [QxMD MEDLINE Link].
Kahaleh MB. Raynaud phenomenon and the vascular disease in scleroderma. Curr Opin Rheumatol. 2004 Nov. 16(6):718-22. [QxMD MEDLINE Link].
Herrick AL. The pathogenesis, diagnosis and treatment of Raynaud phenomenon. Nat Rev Rheumatol. 2012 Aug. 8(8):469-79. [QxMD MEDLINE Link].
Prete M, Fatone MC, Favoino E, Perosa F. Raynaud's phenomenon: from molecular pathogenesis to therapy. Autoimmun Rev. 2014 Jun. 13(6):655-67. [QxMD MEDLINE Link].
Ennis H, Vail A, Wragg E, Taylor A, Moore T, Murray A. A prospective study of systemic sclerosis-related digital ulcers: prevalence, location, and functional impact. Scand J Rheumatol. 2013. 42(6):483-6. [QxMD MEDLINE Link].
Guiducci S, Giacomelli R, Cerinic MM. Vascular complications of scleroderma. Autoimmun Rev. 2007 Sep. 6(8):520-3. [QxMD MEDLINE Link].
Hettema ME, Bootsma H, Kallenberg CG. Macrovascular disease and atherosclerosis in SSc. Rheumatology (Oxford). 2008 May. 47(5):578-83. [QxMD MEDLINE Link].
Chu SY, Chen YJ, Liu CJ, Tseng WC, Lin MW, Hwang CY. Increased risk of acute myocardial infarction in systemic sclerosis: a nationwide population-based study. Am J Med. 2013 Nov. 126(11):982-8. [QxMD MEDLINE Link].
Gyger G, Baron M. Gastrointestinal manifestations of scleroderma: recent progress in evaluation, pathogenesis, and management. Curr Rheumatol Rep. 2012 Feb. 14(1):22-9. [QxMD MEDLINE Link].
Christmann RB, Wells AU, Capelozzi VL, Silver RM. Gastroesophageal reflux incites interstitial lung disease in systemic sclerosis: clinical, radiologic, histopathologic, and treatment evidence. Semin Arthritis Rheum. 2010 Dec. 40(3):241-9. [QxMD MEDLINE Link].
Butt S, Emmanuel A. Systemic sclerosis and the gut. Expert Rev Gastroenterol Hepatol. 2013 May. 7(4):331-9. [QxMD MEDLINE Link].
Di Ciaula A, Covelli M, Berardino M, Wang DQ, Lapadula G, Palasciano G, et al. Gastrointestinal symptoms and motility disorders in patients with systemic scleroderma. BMC Gastroenterol. 2008 Feb 27. 8:7. [QxMD MEDLINE Link]. [Full Text].
Hung EW, Mayes MD, Sharif R, Assassi S, Machicao VI, Hosing C. Gastric antral vascular ectasia and its clinical correlates in patients with early diffuse systemic sclerosis in the SCOT trial. J Rheumatol. 2013 Apr. 40(4):455-60. [QxMD MEDLINE Link].
Ghrénassia E, Avouac J, Khanna D, Derk CT, Distler O, Suliman YA, et al. Prevalence, correlates and outcomes of gastric antral vascular ectasia in systemic sclerosis: a EUSTAR case-control study. J Rheumatol. 2014 Jan. 41(1):99-105. [QxMD MEDLINE Link].
Steen VD. The lung in systemic sclerosis. J Clin Rheumatol. 2005 Feb. 11(1):40-6. [QxMD MEDLINE Link].
Wells AU, Margaritopoulos GA, Antoniou KM, Denton C. Interstitial lung disease in systemic sclerosis. Semin Respir Crit Care Med. 2014 Apr. 35(2):213-21. [QxMD MEDLINE Link].
Chaisson NF, Hassoun PM. Systemic sclerosis-associated pulmonary arterial hypertension. Chest. 2013 Oct. 144(4):1346-56. [QxMD MEDLINE Link].
Clements PJ, Allanore Y, Khanna D, Singh M, Furst DE. Arthritis in systemic sclerosis: systematic review of the literature and suggestions for the performance of future clinical trials in systemic sclerosis arthritis. Semin Arthritis Rheum. 2012 Jun. 41(6):801-14. [QxMD MEDLINE Link].
Avouac J, Clements PJ, Khanna D, Furst DE, Allanore Y. Articular involvement in systemic sclerosis. Rheumatology (Oxford). 2012 Aug. 51(8):1347-56. [QxMD MEDLINE Link].
Randone SB, Guiducci S, Cerinic MM. Musculoskeletal involvement in systemic sclerosis. Best Pract Res Clin Rheumatol. 2008 Apr. 22(2):339-50. [QxMD MEDLINE Link].
Stoenoiu MS, Houssiau FA, Lecouvet FE. Tendon friction rubs in systemic sclerosis: a possible explanation--an ultrasound and magnetic resonance imaging study. Rheumatology (Oxford). 2013 Mar. 52(3):529-33. [QxMD MEDLINE Link].
Doré A, Lucas M, Ivanco D, Medsger TA Jr, Domsic RT. Significance of palpable tendon friction rubs in early diffuse cutaneous systemic sclerosis. Arthritis Care Res (Hoboken). 2013 Aug. 65(8):1385-9. [QxMD MEDLINE Link]. [Full Text].
Steen V. The heart in systemic sclerosis. Curr Rheumatol Rep. 2004 Apr. 6(2):137-40. [QxMD MEDLINE Link].
Desai CS, Lee DC, Shah SJ. Systemic sclerosis and the heart: current diagnosis and management. Curr Opin Rheumatol. 2011 Nov. 23(6):545-54. [QxMD MEDLINE Link].
Meune C, Vignaux O, Kahan A, Allanore Y. Heart involvement in systemic sclerosis: evolving concept and diagnostic methodologies. Arch Cardiovasc Dis. 2010 Jan. 103(1):46-52. [QxMD MEDLINE Link].
Kahan A, Allanore Y. Primary myocardial involvement in systemic sclerosis. Rheumatology (Oxford). 2006 Oct. 45 Suppl 4:iv14-7. [QxMD MEDLINE Link].
Vacca A, Meune C, Gordon J, Chung L, Proudman S, Assassi S. Cardiac arrhythmias and conduction defects in systemic sclerosis. Rheumatology (Oxford). 2013 Nov 15. [QxMD MEDLINE Link].
Chu SY, Chen YJ, Liu CJ, Tseng WC, Lin MW, Hwang CY. Increased risk of acute myocardial infarction in systemic sclerosis: a nationwide population-based study. Am J Med. 2013 Nov. 126(11):982-8. [QxMD MEDLINE Link].
Steen VD. Scleroderma renal crisis. Rheum Dis Clin North Am. 2003 May. 29(2):315-33. [QxMD MEDLINE Link].
Penn H, Howie AJ, Kingdon EJ, Bunn CC, Stratton RJ, Black CM. Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM. 2007 Aug. 100(8):485-94. [QxMD MEDLINE Link].
Steen VD, Syzd A, Johnson JP, Greenberg A, Medsger TA Jr. Kidney disease other than renal crisis in patients with diffuse scleroderma. J Rheumatol. 2005 Apr. 32(4):649-55. [QxMD MEDLINE Link].
Steen VD, Medsger TA Jr. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum. 1998 Sep. 41(9):1613-9. [QxMD MEDLINE Link].
Lally EV, Jimenez SA. Impotence in progressively systemic sclerosis. Ann Intern Med. 1981 Aug. 95(2):150-3. [QxMD MEDLINE Link].
Foocharoen C, Tyndall A, Hachulla E, Rosato E, Allanore Y, Farge-Bancel D, et al. Erectile dysfunction is frequent in systemic sclerosis and associated with severe disease: a study of the EULAR Scleroderma Trial and Research group. Arthritis Res Ther. 2012 Feb 20. 14(1):R37. [QxMD MEDLINE Link]. [Full Text].
Minervini R, Morelli G, Minervini A, Pampaloni S, Tognetti A, Fiorentini L, et al. Bladder involvement in systemic sclerosis: urodynamic and histological evaluation in 23 patients. Eur Urol. 1998. 34(1):47-52. [QxMD MEDLINE Link].
Bhadauria S, Moser DK, Clements PJ, Singh RR, Lachenbruch PA, Pitkin RM. Genital tract abnormalities and female sexual function impairment in systemic sclerosis. Am J Obstet Gynecol. 1995 Feb. 172(2 Pt 1):580-7. [QxMD MEDLINE Link].
Kobak S, Oksel F, Aksu K, Kabasakal Y. The frequency of sicca symptoms and Sjögren's syndrome in patients with systemic sclerosis. Int J Rheum Dis. 2013 Feb. 16(1):88-92. [QxMD MEDLINE Link].
Albilia JB, Lam DK, Blanas N, Clokie CM, Sándor GK. Small mouths ... Big problems? A review of scleroderma and its oral health implications. J Can Dent Assoc. 2007 Nov. 73(9):831-6. [QxMD MEDLINE Link].
Derk CT, Rasheed M, Spiegel JR, Jimenez SA. Increased incidence of carcinoma of the tongue in patients with systemic sclerosis. J Rheumatol. 2005 Apr. 32(4):637-41. [QxMD MEDLINE Link].
Busquets J, Lee Y, Santamarina L, Federman JL, Abel A, Del Galdo F. Acute retinal artery occlusion in systemic sclerosis: a rare manifestation of systemic sclerosis fibroproliferative vasculopathy. Semin Arthritis Rheum. 2013 Oct. 43(2):204-8. [QxMD MEDLINE Link].
Antonelli A, Fallahi P, Ferrari SM, Mancusi C, Giuggioli D, Colaci M, et al. Incidence of thyroid disorders in systemic sclerosis: results from a longitudinal follow-up. J Clin Endocrinol Metab. 2013 Jul. 98(7):E1198-202. [QxMD MEDLINE Link].
Marasini B, Ferrari PA, Solaro N, Selmi C. Thyroid dysfunction in women with systemic sclerosis. Ann N Y Acad Sci. 2007 Jun. 1108:305-11. [QxMD MEDLINE Link].
Amaral TN, Peres FA, Lapa AT, Marques-Neto JF, Appenzeller S. Neurologic involvement in scleroderma: a systematic review. Semin Arthritis Rheum. 2013 Dec. 43(3):335-47. [QxMD MEDLINE Link].
Thombs BD, Taillefer SS, Hudson M, Baron M. Depression in patients with systemic sclerosis: a systematic review of the evidence. Arthritis Rheum. 2007 Aug 15. 57(6):1089-97. [QxMD MEDLINE Link].
Malcarne VL, Fox RS, Mills SD, Gholizadeh S. Psychosocial aspects of systemic sclerosis. Curr Opin Rheumatol. 2013 Nov. 25(6):707-13. [QxMD MEDLINE Link].
Nguyen C, Ranque B, Baubet T, Bérezné A, Mestre-Stanislas C, Rannou F, et al. Clinical, functional and health-related quality of life correlates of clinically significant symptoms of anxiety and depression in patients with systemic sclerosis: a cross-sectional survey. PLoS One. 2014. 9(2):e90484. [QxMD MEDLINE Link]. [Full Text].
Frech TM, Smith G, Reily M, Chamberlain J, Murtaugh MA, Penrod J. Peripheral neuropathy: a complication of systemic sclerosis. Clin Rheumatol. 2013 Jun. 32(6):885-8. [QxMD MEDLINE Link].
Hsu V, Varga J, Schlesinger N. Calcinosis in scleroderma made crystal clear. Curr Opin Rheumatol. 2019 Nov. 31 (6):589-594. [QxMD MEDLINE Link].
Tyndall A, Fistarol S. The differential diagnosis of systemic sclerosis. Curr Opin Rheumatol. 2013 Nov. 25(6):692-9. [QxMD MEDLINE Link].
Yaqub A, Chung L, Rieger KE, Fiorentino DF. Localized cutaneous fibrosing disorders. Rheum Dis Clin North Am. 2013 May. 39(2):347-64. [QxMD MEDLINE Link].
Ferreli C, Gasparini G, Parodi A, Cozzani E, Rongioletti F, Atzori L. Cutaneous Manifestations of Scleroderma and Scleroderma-Like Disorders: a Comprehensive Review. Clin Rev Allergy Immunol. 2017 Dec. 53 (3):306-336. [QxMD MEDLINE Link].
Canady J, Karrer S, Fleck M, Bosserhoff AK. Fibrosing connective tissue disorders of the skin: molecular similarities and distinctions. J Dermatol Sci. 2013 Jun. 70(3):151-8. [QxMD MEDLINE Link].
Zuccaro G Jr. Esophagoscopy and endoscopic esophageal ultrasound in the assessment of esophageal function. Semin Thorac Cardiovasc Surg. 2001 Jul. 13(3):226-33. [QxMD MEDLINE Link].
Chapin R, Hant FN. Imaging of scleroderma. Rheum Dis Clin North Am. 2013 Aug. 39(3):515-46. [QxMD MEDLINE Link].
Strange C, Bolster MB, Roth MD, Silver RM, Theodore A, Goldin J, et al. Bronchoalveolar lavage and response to cyclophosphamide in scleroderma interstitial lung disease. Am J Respir Crit Care Med. 2008 Jan 1. 177(1):91-8. [QxMD MEDLINE Link]. [Full Text].
Kowal-Bielecka O, Kowal K, Highland KB, Silver RM. Bronchoalveolar lavage fluid in scleroderma interstitial lung disease: technical aspects and clinical correlations: review of the literature. Semin Arthritis Rheum. 2010 Aug. 40(1):73-88. [QxMD MEDLINE Link].
van Bon L, Affandi AJ, Broen J, Christmann RB, Marijnissen RJ, Stawski L, et al. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med. 2014 Jan 30. 370(5):433-43. [QxMD MEDLINE Link]. [Full Text].
Allanore Y, Meune C. N-terminal pro brain natriuretic peptide: the new cornerstone of cardiovascular assessment in systemic sclerosis. Clin Exp Rheumatol. 2009 May-Jun. 27(3 Suppl 54):59-63. [QxMD MEDLINE Link].
Chighizola C, Meroni PL, Schreiber BE, Coghlan JG, Denton CP, Ong VH. Role of N-terminal pro-brain natriuretic peptide in detecting clinically significant cardiac involvement in systemic sclerosis patients. Clin Exp Rheumatol. 2012 Mar-Apr. 30(2 Suppl 71):S81-5. [QxMD MEDLINE Link].
Thakkar V, Stevens W, Prior D, Youssef P, Liew D, Gabbay E, et al. The inclusion of N-terminal pro-brain natriuretic peptide in a sensitive screening strategy for systemic sclerosis-related pulmonary arterial hypertension: a cohort study. Arthritis Res Ther. 2013. 15(6):R193. [QxMD MEDLINE Link]. [Full Text].
Hughes M, Lilleker JB, Herrick AL, Chinoy H. Cardiac troponin testing in idiopathic inflammatory myopathies and systemic sclerosis-spectrum disorders: biomarkers to distinguish between primary cardiac involvement and low-grade skeletal muscle disease activity. Ann Rheum Dis. 2015 May. 74 (5):795-8. [QxMD MEDLINE Link]. [Full Text].
Hsu VM, Moreyra AE, Wilson AC, Shinnar M, Shindler DM, Wilson JE, et al. Assessment of pulmonary arterial hypertension in patients with systemic sclerosis: comparison of noninvasive tests with results of right-heart catheterization. J Rheumatol. 2008 Mar. 35(3):458-65. [QxMD MEDLINE Link].
Avouac J, Huscher D, Furst DE, Opitz CF, Distler O, Allanore Y. Expert consensus for performing right heart catheterisation for suspected pulmonary arterial hypertension in systemic sclerosis: a Delphi consensus study with cluster analysis. Ann Rheum Dis. 2014 Jan. 73(1):191-7. [QxMD MEDLINE Link].
Freire V, Bazeli R, Elhai M, Campagna R, Pessis É, Avouac J. Hand and wrist involvement in systemic sclerosis: US features. Radiology. 2013 Dec. 269(3):824-30. [QxMD MEDLINE Link].
Boutry N, Hachulla E, Zanetti-Musielak C, Morel M, Demondion X, Cotten A. Imaging features of musculoskeletal involvement in systemic sclerosis. Eur Radiol. 2007 May. 17(5):1172-80. [QxMD MEDLINE Link].
Cutolo M, Sulli A, Smith V. How to perform and interpret capillaroscopy. Best Pract Res Clin Rheumatol. 2013 Apr. 27(2):237-48. [QxMD MEDLINE Link].
Sulli A, Ruaro B, Alessandri E, Pizzorni C, Cimmino MA, Zampogna G. Correlations between nailfold microangiopathy severity, finger dermal thickness and fingertip blood perfusion in systemic sclerosis patients. Ann Rheum Dis. 2014 Jan. 73(1):247-51. [QxMD MEDLINE Link].
Herrick AL, Cutolo M. Clinical implications from capillaroscopic analysis in patients with Raynaud's phenomenon and systemic sclerosis. Arthritis Rheum. 2010 Sep. 62(9):2595-604. [QxMD MEDLINE Link].
Smith V, Riccieri V, Pizzorni C, Decuman S, Deschepper E, Bonroy C. Nailfold capillaroscopy for prediction of novel future severe organ involvement in systemic sclerosis. J Rheumatol. 2013 Dec. 40(12):2023-8. [QxMD MEDLINE Link].
Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum. 2005 Aug. 35(1):35-42. [QxMD MEDLINE Link].
Mehra S, Walker J, Patterson K, Fritzler MJ. Autoantibodies in systemic sclerosis. Autoimmun Rev. 2013 Jan. 12(3):340-54. [QxMD MEDLINE Link].
Perera A, Fertig N, Lucas M, Rodriguez-Reyna TS, Hu P, Steen VD. Clinical subsets, skin thickness progression rate, and serum antibody levels in systemic sclerosis patients with anti-topoisomerase I antibody. Arthritis Rheum. 2007 Aug. 56(8):2740-6. [QxMD MEDLINE Link].
D'Aoust J, Hudson M, Tatibouet S, Wick J, Mahler M, Baron M, et al. Clinical and Serologic Correlates of Anti-PM/Scl Antibodies in Systemic Sclerosis: A Multicenter Study of 763 Patients. Arthritis Rheumatol. 2014 Jun. 66(6):1608-15. [QxMD MEDLINE Link].
Pignone A, Matucci-Cerinic M, Lombardi A, Fedi R, Fargnoli R, De Dominicis R. High resolution computed tomography in systemic sclerosis. Real diagnostic utilities in the assessment of pulmonary involvement and comparison with other modalities of lung investigation. Clin Rheumatol. 1992 Dec. 11(4):465-72. [QxMD MEDLINE Link].
Khanna D, Tseng CH, Farmani N, Steen V, Furst DE, Clements PJ. Clinical course of lung physiology in patients with scleroderma and interstitial lung disease: analysis of the Scleroderma Lung Study Placebo Group. Arthritis Rheum. 2011 Oct. 63(10):3078-85. [QxMD MEDLINE Link].
Hudson M, Assayag D, Caron M, Fox BD, Hirsch A, Steele R. Comparison of different measures of diffusing capacity for carbon monoxide (DLCO) in systemic sclerosis. Clin Rheumatol. 2013 Oct. 32(10):1467-74. [QxMD MEDLINE Link].
Schreiber BE, Valerio CJ, Keir GJ, Handler C, Wells AU, Denton CP. Improving the detection of pulmonary hypertension in systemic sclerosis using pulmonary function tests. Arthritis Rheum. 2011 Nov. 63(11):3531-9. [QxMD MEDLINE Link].
Steen VD, Graham G, Conte C, Owens G, Medsger TA Jr. Isolated diffusing capacity reduction in systemic sclerosis. Arthritis Rheum. 1992 Jul. 35(7):765-70. [QxMD MEDLINE Link].
Codullo V, Caporali R, Cuomo G, Ghio S, D'Alto M, Fusetti C. Stress Doppler echocardiography in systemic sclerosis: evidence for a role in the prediction of pulmonary hypertension. Arthritis Rheum. 2013 Sep. 65(9):2403-11. [QxMD MEDLINE Link].
Draeger HT, Assassi S, Sharif R, Gonzalez EB, Harper BE, Arnett FC, et al. Right bundle branch block: a predictor of mortality in early systemic sclerosis. PLoS One. 2013. 8(10):e78808. [QxMD MEDLINE Link]. [Full Text].
Nordin A, Björnådal L, Larsson A, Svenungsson E, Jensen-Urstad K. Electrocardiography in 110 patients with systemic sclerosis: a cross-sectional comparison with population-based controls. Scand J Rheumatol. 2014. 43(3):221-5. [QxMD MEDLINE Link].
Thonhofer R, Siegel C, Trummer M, Graninger W. Early endoscopy in systemic sclerosis without gastrointestinal symptoms. Rheumatol Int. 2012 Jan. 32(1):165-8. [QxMD MEDLINE Link].
Lahcene M, Oumnia N, Matougui N, Boudjella M, Tebaibia A, Touchene B. Esophageal involvement in scleroderma: clinical, endoscopic, and manometric features. ISRN Rheumatol. 2011. 2011:325826. [QxMD MEDLINE Link].
Denton CP, Ong VH. Targeted therapies for systemic sclerosis. Nat Rev Rheumatol. 2013 Aug. 9(8):451-64. [QxMD MEDLINE Link].
Bhattacharyya S, Wei J, Varga J. Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol. 2012 Jan. 8(1):42-54. [QxMD MEDLINE Link].
Cappelli S, Guiducci S, Bellando Randone S, Matucci Cerinic M. Immunosuppression for interstitial lung disease in systemic sclerosis. Eur Respir Rev. 2013 Sep 1. 22(129):236-43. [QxMD MEDLINE Link].
Frech TM, Shanmugam VK, Shah AA, Assassi S, Gordon JK, Hant FN. Treatment of early diffuse systemic sclerosis skin disease. Clin Exp Rheumatol. 2013 Mar-Apr. 31(2 Suppl 76):166-71. [QxMD MEDLINE Link].
Nihtyanova SI, Ong VH, Denton CP. Current management strategies for systemic sclerosis. Clin Exp Rheumatol. 2014 Mar-Apr. 32(2 Suppl 81):156-64. [QxMD MEDLINE Link].
Denton CP. Systemic sclerosis: from pathogenesis to targeted therapy. Clin Exp Rheumatol. 2015 Sep-Oct. 33 (4 Suppl 92):3-7. [QxMD MEDLINE Link].
A Study of the Efficacy and Safety of Tocilizumab in Participants With Systemic Sclerosis (SSc) (focuSSced). ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT02453256. April 16, 2019; Accessed: September 9, 2019.
Khanna D, Lin CJF, Goldin J, et al. OP0245 PRESERVATION OF LUNG FUNCTION OBSERVED IN A PHASE 3 RANDOMIZED CONTROLLED TRIAL OF TOCILIZUMAB FOR THE TREATMENT OF EARLY SSC. Ann Rheum Dis. June 14, 2019. 78 Suppl 2:202. [Full Text].
Freeman S. Tocilizumab preserves lung function in systemic sclerosis. MDedge. Available at https://www.mdedge.com/rheumatology/article/203584/lupus-connective-tissue-diseases/tocilizumab-preserves-lung-function. June 26, 2019; Accessed: June 24, 2020.
van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de Putte LB. Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial. Br J Rheumatol. 1996 Apr. 35(4):364-72. [QxMD MEDLINE Link].
Pope JE, Bellamy N, Seibold JR, Baron M, Ellman M, Carette S. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 2001 Jun. 44(6):1351-8. [QxMD MEDLINE Link].
Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006 Jun 22. 354(25):2655-66. [QxMD MEDLINE Link].
Nannini C, West CP, Erwin PJ, Matteson EL. Effects of cyclophosphamide on pulmonary function in patients with scleroderma and interstitial lung disease: a systematic review and meta-analysis of randomized controlled trials and observational prospective cohort studies. Arthritis Res Ther. 2008. 10(5):R124. [QxMD MEDLINE Link]. [Full Text].
Derk CT, Grace E, Shenin M, Naik M, Schulz S, Xiong W. A prospective open-label study of mycophenolate mofetil for the treatment of diffuse systemic sclerosis. Rheumatology (Oxford). 2009 Dec. 48(12):1595-9. [QxMD MEDLINE Link].
Mendoza FA, Nagle SJ, Lee JB, Jimenez SA. A prospective observational study of mycophenolate mofetil treatment in progressive diffuse cutaneous systemic sclerosis of recent onset. J Rheumatol. 2012 Jun. 39(6):1241-7. [QxMD MEDLINE Link].
Le EN, Wigley FM, Shah AA, Boin F, Hummers LK. Long-term experience of mycophenolate mofetil for treatment of diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2011 Jun. 70(6):1104-7. [QxMD MEDLINE Link].
Derk CT, Huaman G, Jimenez SA. A retrospective randomly selected cohort study of D-penicillamine treatment in rapidly progressive diffuse cutaneous systemic sclerosis of recent onset. Br J Dermatol. 2008 May. 158(5):1063-8. [QxMD MEDLINE Link].
Clements PJ, Furst DE, Wong WK, Mayes M, White B, Wigley F. High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, double-blind, randomized, controlled clinical trial. Arthritis Rheum. 1999 Jun. 42(6):1194-203. [QxMD MEDLINE Link].
Smith V, Piette Y, van Praet JT, Decuman S, Deschepper E, Elewaut D, et al. Two-year results of an open pilot study of a 2-treatment course with rituximab in patients with early systemic sclerosis with diffuse skin involvement. J Rheumatol. 2013 Jan. 40(1):52-7. [QxMD MEDLINE Link].
Jordan S, Distler JH, Maurer B, Huscher D, van Laar JM, Allanore Y, et al. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 2015 Jun. 74 (6):1188-94. [QxMD MEDLINE Link].
Moazedi-Fuerst FC, Kielhauser SM, Brickmann K, Hermann J, Lutfi A, Meilinger M. Rituximab for systemic sclerosis: arrest of pulmonary disease progression in five cases. Results of a lower dosage and shorter interval regimen. Scand J Rheumatol. 2014. 43(3):257-8. [QxMD MEDLINE Link].
Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Paliogianni F, Sirinian C, et al. Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis. Clin Exp Rheumatol. 2012 Mar-Apr. 30(2 Suppl 71):S17-22. [QxMD MEDLINE Link].
Keyal U, Bhatta AK, Wang XL. UVA1 a promising approach for scleroderma. Am J Transl Res. 2017. 9 (9):4280-4287. [QxMD MEDLINE Link]. [Full Text].
Naraghi K, van Laar JM. Update on stem cell transplantation for systemic sclerosis: recent trial results. Curr Rheumatol Rep. 2013. 15(5):326.
van Laar JM, Sullivan K. Stem cell transplantation in systemic sclerosis. Curr Opin Rheumatol. 2013 Nov. 25(6):719-25. [QxMD MEDLINE Link].
Milanetti F, Bucha J, Testori A, Burt RK. Autologous hematopoietic stem cell transplantation for systemic sclerosis. Curr Stem Cell Res Ther. 2011 Mar. 6(1):16-28. [QxMD MEDLINE Link].
Burt RK, Milanetti F. Hematopoietic stem cell transplantation for systemic sclerosis: history and current status. Curr Opin Rheumatol. 2011 Nov. 23(6):519-29. [QxMD MEDLINE Link].
van Laar JM, et al; EBMT/EULAR Scleroderma Study Group. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014 Jun 25. 311 (24):2490-8. [QxMD MEDLINE Link].
Sullivan KM, et al; SCOT Study Investigators. Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. N Engl J Med. 2018 Jan 4. 378 (1):35-47. [QxMD MEDLINE Link]. [Full Text].
Sullivan KM, Shah A, Sarantopoulos S, Furst DE. Review: Hematopoietic Stem Cell Transplantation for Scleroderma: Effective Immunomodulatory Therapy for Patients With Pulmonary Involvement. Arthritis Rheumatol. 2016 Oct. 68 (10):2361-71. [QxMD MEDLINE Link]. [Full Text].
Postlethwaite AE, Wong WK, Clements P, Chatterjee S, Fessler BJ, Kang AH, et al. A multicenter, randomized, double-blind, placebo-controlled trial of oral type I collagen treatment in patients with diffuse cutaneous systemic sclerosis: I. oral type I collagen does not improve skin in all patients, but may improve skin in late-phase disease. Arthritis Rheum. 2008 Jun. 58(6):1810-22. [QxMD MEDLINE Link].
Khanna D, Clements PJ, Furst DE, Korn JH, Ellman M, Rothfield N. Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2009 Apr. 60(4):1102-11. [QxMD MEDLINE Link].
Black CM, Silman AJ, Herrick AI, Denton CP, Wilson H, Newman J, et al. Interferon-alpha does not improve outcome at one year in patients with diffuse cutaneous scleroderma: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 1999 Feb. 42(2):299-305. [QxMD MEDLINE Link].
Denton CP, Merkel PA, Furst DE, Khanna D, Emery P, Hsu VM, et al. Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum. 2007 Jan. 56(1):323-33. [QxMD MEDLINE Link].
Frech TM, Baron M. Understanding itch in systemic sclerosis in order to improve patient quality of life. Clin Exp Rheumatol. 2013 Mar-Apr. 31(2 Suppl 76):81-8. [QxMD MEDLINE Link].
Herrick AL. Management of Raynaud's phenomenon and digital ischemia. Curr Rheumatol Rep. 2013 Jan. 15(1):303. [QxMD MEDLINE Link].
Fries R, Shariat K, von Wilmowsky H, Böhm M. Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy. Circulation. 2005 Nov 8. 112(19):2980-5. [QxMD MEDLINE Link].
Brueckner CS, Becker MO, Kroencke T, Huscher D, Scherer HU, Worm M. Effect of sildenafil on digital ulcers in systemic sclerosis: analysis from a single centre pilot study. Ann Rheum Dis. 2010 Aug. 69(8):1475-8. [QxMD MEDLINE Link].
Della Rossa A, Doveri M, D'Ascanio A, Tavoni A, Consensi A, Neri R, et al. Oral sildenafil in skin ulcers secondary to systemic sclerosis. Scand J Rheumatol. 2011. 40(4):323-5. [QxMD MEDLINE Link].
Hummers LK, Wigley FM. Management of Raynaud's phenomenon and digital ischemic lesions in scleroderma. Rheum Dis Clin North Am. 2003 May. 29(2):293-313. [QxMD MEDLINE Link].
Wigley FM, Wise RA, Seibold JR, McCloskey DA, Kujala G, Medsger TA Jr. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study. Ann Intern Med. 1994 Feb 1. 120(3):199-206. [QxMD MEDLINE Link].
Shah AA, Schiopu E, Hummers LK, Wade M, Phillips K, Anderson C, et al. Open label study of escalating doses of oral treprostinil diethanolamine in patients with systemic sclerosis and digital ischemia: pharmacokinetics and correlation with digital perfusion. Arthritis Res Ther. 2013 Apr 18. 15(2):R54. [QxMD MEDLINE Link].
Tomaino MM, Goitz RJ, Medsger TA. Surgery for ischemic pain and Raynaud's' phenomenon in scleroderma: a description of treatment protocol and evaluation of results. Microsurgery. 2001. 21(3):75-9. [QxMD MEDLINE Link].
Romaniello A, Viola G, Salsano F, Rosato E. In systemic sclerosis patients, bosentan is safe and effective for digital ulcer prevention and it seems to attenuate the development of pulmonary arterial hypertension. Rheumatology (Oxford). 2014 Mar. 53(3):570-1. [QxMD MEDLINE Link].
Agard C, Carpentier P, Mouthon L, Clerson P, Gressin V, Bérezné A. Use of bosentan for digital ulcers related to systemic sclerosis: a real-life retrospective French study of 89 patients treated since specific approval. Scand J Rheumatol. 2014 Apr 11. [QxMD MEDLINE Link].
Trombetta AC, Pizzorni C, Ruaro B, Paolino S, Sulli A, Smith V, et al. Effects of Longterm Treatment with Bosentan and Iloprost on Nailfold Absolute Capillary Number, Fingertip Blood Perfusion, and Clinical Status in Systemic Sclerosis. J Rheumatol. 2016 Oct 1. 7(11):1487-501. [QxMD MEDLINE Link].
Parisi S, Peroni CL, Laganà A, Scarati M, Ambrogio F, Bruzzone M, et al. Efficacy of ambrisentan in the treatment of digital ulcers in patients with systemic sclerosis: a preliminary study. Rheumatology (Oxford). 2013 Jun. 52(6):1142-4. [QxMD MEDLINE Link].
Patel T, McKeage K. Macitentan: first global approval. Drugs. 2014 Jan. 74(1):127-33. [QxMD MEDLINE Link].
Sallam H, McNearney TA, Chen JD. Systematic review: pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis (scleroderma). Aliment Pharmacol Ther. 2006 Mar 15. 23(6):691-712. [QxMD MEDLINE Link].
Forbes A, Marie I. Gastrointestinal complications: the most frequent internal complications of systemic sclerosis. Rheumatology (Oxford). 2009 Jun. 48 Suppl 3:iii36-9. [QxMD MEDLINE Link].
Sakkas LI, Simopoulou T, Daoussis D, Liossis SN, Potamianos S. Intestinal Involvement in Systemic Sclerosis: A Clinical Review. Dig Dis Sci. 2018 Apr. 63 (4):834-844. [QxMD MEDLINE Link].
Lota HK, Wells AU. The evolving pharmacotherapy of pulmonary fibrosis. Expert Opin Pharmacother. 2013 Jan. 14(1):79-89. [QxMD MEDLINE Link].
Cappelli S, Guiducci S, Bellando Randone S, Matucci Cerinic M. Immunosuppression for interstitial lung disease in systemic sclerosis. Eur Respir Rev. 2013 Sep 1. 22(129):236-43. [QxMD MEDLINE Link].
Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 2006 Dec. 54(12):3962-70. [QxMD MEDLINE Link].
Gerbino AJ, Goss CH, Molitor JA. Effect of mycophenolate mofetil on pulmonary function in scleroderma-associated interstitial lung disease. Chest. 2008 Feb. 133(2):455-60. [QxMD MEDLINE Link].
Owen C, Ngian GS, Elford K, Moore O, Stevens W, Nikpour M, et al. Mycophenolate mofetil is an effective and safe option for the management of systemic sclerosis-associated interstitial lung disease: results from the Australian Scleroderma Cohort Study. Clin Exp Rheumatol. 2016 Sep-Oct. 34 Suppl 100 (5):170-176. [QxMD MEDLINE Link].
Tashkin DP, et al; Sclerodema Lung Study II Investigators. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016 Sep. 4 (9):708-719. [QxMD MEDLINE Link]. [Full Text].
Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD, et al. Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease. N Engl J Med. 2019 Jun 27. 380 (26):2518-2528. [QxMD MEDLINE Link].
Khanna D, Lin CJF, Furst DE, Wagner B, Zucchetto M, Raghu G, et al. Long-Term Safety and Efficacy of Tocilizumab in Early Systemic Sclerosis-Interstitial Lung Disease: Open-Label Extension of a Phase 3 Randomized Controlled Trial. Am J Respir Crit Care Med. 2022 Mar 15. 205 (6):674-684. [QxMD MEDLINE Link].
Brooks M. FDA Clears Two-Drug Combo as First-Line Treatment for PAH. Medscape Medical News. Available at http://www.medscape.com/viewarticle/852129. October 6, 2015; Accessed: October 23, 2015.
Hassoun PM, Zamanian RT, Damico R, Lechtzin N, Khair R, Kolb TM, et al. Ambrisentan and Tadalafil Upfront Combination Therapy in Scleroderma-Associated PAH. Am J Respir Crit Care Med. 2015 Sep 11. 47 (1-2):63-7. [QxMD MEDLINE Link].
Johnson SR, Granton JT, Tomlinson GA, Grosbein HA, Le T, Lee P, et al. Warfarin in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension. A Bayesian approach to evaluating treatment for uncommon disease. J Rheumatol. 2012 Feb. 39(2):276-85. [QxMD MEDLINE Link].
Santos Cardozo Roque LC, Tenório ADS, de Aquino LT, Ferreira RDS, Duarte ALBP, Dantas AT. Joint mobilization and therapeutic exercises in the hands of patients with systemic sclerosis: A preliminary randomized controlled trial. Clin Rehabil. 2022 Jan. 36 (1):113-124. [QxMD MEDLINE Link].
Murphy SL, Barber M, Huang S, Sabbagh M, Cutter G, Khanna D. Intensive and app-delivered occupational therapy to improve upper extremity function in early diffuse cutaneous systemic sclerosis: a pilot two-arm trial. Rheumatology (Oxford). 2021 Nov 3. 60 (11):5002-5011. [QxMD MEDLINE Link].
Waszczykowski M, Dziankowska-Bartkowiak B, Podgórski M, Fabiś J, Waszczykowska A. Role and effectiveness of complex and supervised rehabilitation on overall and hand function in systemic sclerosis patients-one-year follow-up study. Sci Rep. 2021 Jul 26. 11 (1):15174. [QxMD MEDLINE Link].
Pieper PG, Lameijer H, Hoendermis ES. Pregnancy and pulmonary hypertension. Best Pract Res Clin Obstet Gynaecol. 2014 May. 28(4):579-91. [QxMD MEDLINE Link].
Groseanu L, Bojinca V, Gudu T, Saulescu I, Predeteanu D, Balanescu A, et al. Low vitamin D status in systemic sclerosis and the impact on disease phenotype. Eur J Rheumatol. 2016 Jun. 3 (2):50-55. [QxMD MEDLINE Link].
Merkel PA, Silliman NP, Denton CP, Furst DE, Khanna D, Emery P, et al. Validity, reliability, and feasibility of durometer measurements of scleroderma skin disease in a multicenter treatment trial. Arthritis Rheum. 2008 May 15. 59(5):699-705. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

Scleroderma: Tightening of the skin in the face, with a characteristic beaklike facies and paucity of wrinkles.
Scleroderma: Sclerodactyly with digital ulceration, loss of skin creases, joint contractures, and sparse hair.
Scleroderma: Anterior chest demonstrating salt-and-pepper hypopigmentation and diffuse hyperpigmentation in a white woman.
A radiograph of the distal digits demonstrating calcinosis and distal phalanx reabsorption (acral osteolysis).
Scleroderma: Fingernail capillary bed demonstrating capillary dropout with large dilated vessels.
Lung biopsy demonstrating severe interstitial fibrosis and medial fibrosis and smooth muscle hyperplasia of a pulmonary arteriole compatible with pulmonary hypertension.
Lung biopsy demonstrating expansion of the interstitium of the lung by fibrous tissue along with chronic inflammatory cells.
Scleroderma: Barium swallow demonstrating reflux into the distal esophagus, as well as an accordion appearance in the duodenum.
Skin biopsy showing extensive fibrosis. The biopsy has a square morphology, which reflects the rigidity of the tissue biopsy specimen due to striking pan-dermal sclerosis. In addition, the fibrosing reaction extends into the panniculus. The number of adnexal structures is reduced, another characteristic feature of scleroderma. A significant inflammatory cell infiltrate is not observed. This is in contradistinction to morphea, in which a prominent inflammatory cell infiltrate is present.
Skin biopsy showing severe fibrosis. The fibrosis reflects a widening of collagen bundles in concert with an increase in the number of collagen fibers. Note the superimposed deposition of the newly synthesized delicate collagen bundles interposed between the preexisting collagen bundles, the latter appearing wide and manifesting a hyalinized morphology.
Overall scheme illustrating a proposed sequence of events involved in tissue fibrosis and fibroproliferative vasculopathy in systemic sclerosis. An unknown causative agent induces activation of immune and inflammatory cells in genetically predisposed hosts, resulting in chronic inflammation. Activated inflammatory and immune cells secrete cytokines, chemokines, and growth factors, which cause fibroblast activation, differentiation of endothelial and epithelial cells into myofibroblasts, and recruitment of fibrocytes from the bone marrow and the peripheral blood. The activated myofibroblasts produce exaggerated amounts of extracellular matrix, resulting in tissue fibrosis.

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Table 1. ACR/EULAR Revised Systemic Sclerosis Classification Criteria

Table 1. ACR/EULAR Revised Systemic Sclerosis Classification Criteria

Item	Sub-item(s)	Score*
Skin thickening of the fingers of both hands extending proximally to the metacarpophalangeal joints (presence of this criterion is sufficient criterion for SSc classification)	None	9
Skin thickening of the fingers (count the higher score only)	Puffy fingers	2
	Sclerodactyly (distal to the metacarpophalangeal joints but proximal to the proximal interphalangeal joints)	4
Fingertip lesions (count the higher score only)	Digital tip ulcers	2
Fingertip lesions (count the higher score only)	Fingertip pitting scars	3
Telangiectasia	None	2
Abnormal nailfold capillaries	None	2
Pulmonary arterial hypertension and/or interstitial lung disease (maximum score is 2)	Pulmonary arterial hypertension	2
	Interstitial lung disease	2
Raynaud phenomenon	None	3
Systemic sclerosis–related autoantibodies (maximum score is 3)	Anticentromere	3
	Anti–topoisomerase I	3
	Anti–RNA polymerase III	3
The total score is determined by adding the maximum score in each category. Patients with a total score ≥ 9 are classified as having definite systemic sclerosis (modified from van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum*. Nov 2013;65(11):2737-47.^[1])

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Author

Abhishek Nandan, MD Associate Professor of Medicine, Associate Program Director for Rheumatology Fellowship, Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Virginia Commonwealth University School of Medicine; Staff Physician, Richmond VA Medical Center, Central Virginia Veterans Health Care System

Abhishek Nandan, MD is a member of the following medical societies: American College of Rheumatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Elliot Goldberg, MD Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Lewis Katz School of Medicine at Temple University

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

John Varga, MD Professor, Department of Internal Medicine, Division of Rheumatology, Northwestern University

John Varga, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, Central Society for Clinical and Translational Research, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Sergio A Jimenez, MD, MACR, FACP, FRCP(UK Hon) Professor and Co-Director, Jefferson Institute of Molecular Medicine, Director, Connective Tissue Diseases Section, Director, The Scleroderma Center, Sidney Kimmel Medical College of Thomas Jefferson University

Sergio A Jimenez, MD, MACR, FACP, FRCP(UK Hon) is a member of the following medical societies: American College of Physicians, American College of Rheumatology, American Society for Biochemistry and Molecular Biology, Royal College of Physicians, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Fabian A Mendoza-Ballesteros, MD, FACR Assistant Professor of Medicine, Division of Rheumatology, Jefferson Institute of Molecular Medicine; Associate Director of The Scleroderma Center, Director of Scleroderma Program, Sidney Kimmel Medical College of Thomas Jefferson University

Fabian A Mendoza-Ballesteros, MD, FACR is a member of the following medical societies: American College of Rheumatology

Disclosure: Nothing to disclose.

Acknowledgements

Patrick M Cronin, DO, FACR Clinical Associate Professor of Medicine, Department of Medicine, Division of Rheumatology, University of Pennsylvania Health System, Pennsylvania Hospital

Patrick M Cronin, DO, FACR is a member of the following medical societies: American College of Rheumatology, American Osteopathic Association, and Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Andrew S Koenig, DO Consulting Staff, Division of Rheumatology, Rancoccas Hospital

Andrew S Koenig, DO is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American College of Rheumatology, and American Osteopathic Association

Disclosure: Nothing to disclose.

Marie Spevak O'Brien, DO Assistant Clinical Professor of Medicine, Arthritis and Rheumatology, Lehigh Valley Physician Group

Marie Spevak O'Brien, DO is a member of the following medical societies: American College of Physicians, American College of Rheumatology, American Medical Association, American Osteopathic Association, International Society for Clinical Densitometry, and Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Acknowledgments

The assistance of Kenneth Brown in the preparation of this manuscript is gratefully acknowledged.

Sergio A Jimenez, MD, was recipient of NIH/NIAMS grant #RO-1 AR19616.