Highlights & Basics
- Systemic sclerosis (SSc; also known as scleroderma) is a noncontagious, chronic, multisystem disease.
- Initial symptoms are nonspecific and include fatigue, vague musculoskeletal complaints, diffuse swelling of hands, and Raynaud phenomenon.
- Disease course is variable, but the condition rarely subsides spontaneously.
- There are two main subtypes of SSc: limited cutaneous SSc and diffuse cutaneous SSc. The limited cutaneous form tends to have less severe internal organ involvement and a better prognosis, but should still be followed up closely for possible complications.
- Clinical course is determined by extent of vascular and fibrosing complications. Vascular involvement includes Raynaud phenomenon, ischemic digital ulcers, hypertensive crisis, and pulmonary arterial hypertension. Fibrosis can involve lungs, heart, and gastrointestinal tract.
Quick Reference
History & Exam
Key Factors
Other Factors
Diagnostics Tests
Treatment Options
Definition
Epidemiology
Etiology
Pathophysiology
Images
Digital pits without ulcers
Hand demonstrating sclerodactyly with finger curling, shiny skin at the fingers, and telangiectasias
Telangiectasias on the hand
Telangiectasias on the fingers
Digital tip infarction
Digital tip infarction
Hands demonstrating Raynaud phenomenon
Fingers demonstrating sclerodactyly with finger curling, shiny skin at the fingers, and telangiectasias
Late-stage sclerodactyly with contractures due to severe skin tightening
Late-stage sclerodactyly with contractures due to severe skin tightening
Digital tip infarction
Citations
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. Ann Rheum Dis. 2013 Nov;72(11):1747-55.[Abstract][Full Text]
Parodis I, Girard-Guyonvarc'h C, Arnaud L, et al. EULAR recommendations for the non-pharmacological management of systemic lupus erythematosus and systemic sclerosis. Ann Rheum Dis. 2024 May 15;83(6):720-9.[Abstract][Full Text]
Del Galdo F, Lescoat A, Conaghan PG, et al. EULAR recommendations for the treatment of systemic sclerosis: 2023 update. Ann Rheum Dis. 2025 Jan;84(1):29-40.[Abstract][Full Text]
American College of Rheumatology. 2023 American College of Rheumatology (ACR) guideline for the treatment of interstitial lung disease in people with systemic autoimmune rheumatic disease. Aug 2023 [internet publication].[Full Text]
1. 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. Ann Rheum Dis. 2013 Nov;72(11):1747-55.[Abstract][Full Text]
2. Hoffmann-Vold AM, Gunnarsson R, Garen T, et al. Performance of the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for systemic sclerosis (SSc) in large, well-defined cohorts of SSc and mixed connective tissue disease. J Rheumatol. 2015 Jan;42(1):60-3.[Abstract]
3. Jordan S, Maurer B, Toniolo M, et al. Performance of the new ACR/EULAR classification criteria for systemic sclerosis in clinical practice. Rheumatology (Oxford). 2015 Aug;54(8):1454-8.[Abstract]
4. LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets, and pathogenesis. J Rheumatol. 1988 Feb;15(2):202-5.[Abstract]
5. Good SD, Lee JY, Johnson RE, et al. A scoping review of the epidemiology of systemic sclerosis and its organ manifestations: 2018-2024. Curr Opin Rheumatol. 2025 Mar 1;37(2):103-12.[Abstract]
6. Mayes MD, Reveille JD. Epidemiology, demographics, and genetics. In: Clements P, Furst D, ed. Systemic sclerosis, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:89-93.
7. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part I. Arthritis Rheum. 2008 Jan;58(1):15-25.[Abstract]
8. Zhou X, Tan FK, Xiong M, et al. Monozygotic twins clinically discordant for scleroderma show concordance for fibroblast gene expression profiles. Arthritis Rheum. 2005 Oct;52(10):3305-14.[Abstract][Full Text]
9. Kuwana M, Feghali CA, Medsger TA Jr, et al. Autoreactive T cells to topoisomerase I in monozygotic twins discordant for systemic sclerosis. Arthritis Rheum. 2001 Jul;44(7):1654-9.[Abstract]
10. Arnett FC, Cho M, Chatterjee S, et al. Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts. Arthritis Rheum. 2001 Jun;44(6):1359-62.[Abstract][Full Text]
11. Tan FK, Stivers DN, Arnett FC, et al. HLA haplotypes and microsatellite polymorphisms in and around the major histocompatibility complex region in a Native American population with a high prevalence of scleroderma (systemic sclerosis). Tissue Antigens. 1999 Jan;53(1):74-80.[Abstract]
12. Mehra S, Walker J, Patterson K, et al. Autoantibodies in systemic sclerosis. Autoimmun Rev. 2013 Jan;12(3):340-54.[Abstract]
13. Kayser C, Fritzler MJ. Autoantibodies in systemic sclerosis: unanswered questions. Front Immunol. 2015;6:167.[Abstract][Full Text]
14. Nietert PJ, Silver RM. Systemic sclerosis: environmental and occupational risk factors. Curr Opin Rheumatol. 2000 Nov;12(6):520-6.[Abstract]
15. Harris ED Jr, Budd RC, Firestein GS, et al. Kelley's textbook of rheumatology. 7th Ed. Elsevier Saunders; 2005.
16. Assassi S, Radstake TR, Mayes MD, et al. Genetics of scleroderma: implications for personalized medicine? BMC Med. 2013 Jan 11;11:9.[Abstract][Full Text]
17. Kallenberg CG. Early detection of connective tissue disease in patients with Raynaud's phenomenon. Rheum Dis Clin North Am. 1990 Feb;16(1):11-30.[Abstract]
18. Kallenberg CG Wouda AA, Hoet MH, et al. Development of connective tissue disease in patients with Raynaud's phenomenon: a six year follow up with emphasis on the predictive value of antinuclear antibodies as detected by immunoblotting. Ann Rheum Dis. 1990 Feb;16(1):11-30.[Abstract]
19. American College of Rheumatology. 2023 American College of Rheumatology (ACR) guideline for the screening and monitoring of interstitial lung disease in people with systemic autoimmune rheumatic disease. Aug 2023 [internet publication].[Full Text]
20. Podolanczuk AJ, Hunninghake GM, Wilson KC, et al. Approach to the evaluation and management of interstitial lung abnormalities: an official American Thoracic Society clinical statement. Am J Respir Crit Care Med. 2025 Jul;211(7):1132-55.[Abstract][Full Text]
21. Leroy EC, Medsger TA. Raynaud's phenomenon: a proposal for classification. Clin Exp Rheumatol. 1992 Sep-Oct;10(5):485-8.[Abstract]
22. Wigley FM. Clinical practice: Raynaud's phenomenon. N Eng J Med. 2002 Sep 26;347(13):1001-8.[Abstract]
23. Turner R, Lipshutz W, Miller W, et al. Esophageal dysfunction in collagen vascular disease. Am J Med Sci. 1973 Mar;265(3):191-9.[Abstract]
24. Akesson A, Wollheim FA. Organ manifestations in 100 patients with progressive systemic sclerosis: a comparison between the CREST syndrome and diffuse scleroderma. Br J Rheumatol. 1989 Aug;28(4):281-6.[Abstract]
25. Penn H, Howie AJ, Kingdon EJ, et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM. 2007 Aug;100(8):485-94.[Abstract][Full Text]
26. Bryan C, Knight C, Black CM, et al. Prediction of five-year survival following presentation with scleroderma: development of a simple model using three disease factors at first visit. Arthritis Rheum. 1999 Dec;42(12):2660-5.[Abstract][Full Text]
27. Deswal A, Follansbee WP. Cardiac involvement in scleroderma. Rheum Dis Clin North Am. 1996 Nov;22(4):841-60.[Abstract]
28. Parodis I, Girard-Guyonvarc'h C, Arnaud L, et al. EULAR recommendations for the non-pharmacological management of systemic lupus erythematosus and systemic sclerosis. Ann Rheum Dis. 2024 May 15;83(6):720-9.[Abstract][Full Text]
29. Thompson AE, Shea B, Welch V, et al. Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis. Arthritis Rheum. 2001;44(8):1841-7.[Abstract][Full Text]
30. Del Galdo F, Lescoat A, Conaghan PG, et al. EULAR recommendations for the treatment of systemic sclerosis: 2023 update. Ann Rheum Dis. 2025 Jan;84(1):29-40.[Abstract][Full Text]
31. Roustit M, Blaise S, Allanore Y, et al. Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud's phenomenon: systematic review and meta-analysis of randomised trials. Ann Rheum Dis. 2013 Oct;72(10):1696-9.[Abstract][Full Text]
32. Hachulla E, Hatron PY, Carpentier P, et al. Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: the placebo-controlled SEDUCE study. Ann Rheum Dis. 2016 Jun;75(6):1009-15.[Full Text]
33. Matucci-Cerinic M, Denton CP, Furst DE, et al. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2011 Jan;70(1):32-8.[Abstract][Full Text]
34. Pope J, Fenlon D, Thompson A, et al. Iloprost and cisaprost for Raynaud's phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev. 2000 Apr 27;1998(2):CD000953.[Abstract][Full Text]
35. Hughes M, Allanore Y, El Aoufy K, et al. A practical approach to the management of digital ulcers in patients with systemic sclerosis: a narrative review. JAMA Dermatol. 2021 Jul 1;157(7):851-8.[Abstract][Full Text]
36. Valentini G, Paone C, La Montagna G, et al. Low-dose intravenous cyclophosphamide in systemic sclerosis: an open prospective efficacy study in patients with early diffuse disease. Scand J Rheumatol. 2006 Jan-Feb;35(1):35-8.[Abstract]
37. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006 Jun 22;354(25):2655-66.[Abstract][Full Text]
38. Tian X, An P, Liu R, et al. Efficacy of cyclophosphamide for skin fibrosis in systemic sclerosis: a systematic review and single-arm meta-analysis. Eur J Clin Pharmacol. 2025 Jun;81(6):863-74.[Abstract]
39. Ohta R, Horinishi Y, Sano C, et al. Efficacy of mycophenolate mofetil in treating skin fibrosis in systemic sclerosis: a systematic review and meta-analysis. J Clin Med. 2025 Jun 12;14(12):4187.[Abstract][Full Text]
40. Pope JE, Bellamy N, Seibold JR, et al. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 2001 Jun;44(6):1351-8.[Abstract]
41. van den Hoogen FH, Boerbooms AM, Swaak AJ, et al. 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.[Abstract]
42. Johnson SR, Feldman BM, Pope JE, et al. Shifting our thinking about uncommon disease trials: the case of methotrexate in scleroderma. J Rheumatol. 2009 Feb;36(2):323-9.[Abstract]
43. Macrea M, Ghazipura M, Herman D, et al. Rituximab in patients with systemic sclerosis-associated interstitial lung disease: a systematic review and meta-analysis. Ann Am Thorac Soc. 2024 Feb;21(2):317-27.[Abstract]
44. Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016 Jun 25;387(10038):2630-40.[Abstract]
45. Khanna D, Lin CJF, Furst DE, et al. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2020 Oct;8(10):963-74.[Abstract]
46. Bruera S, Sidanmat H, Molony DA, et al. Stem cell transplantation for systemic sclerosis. Cochrane Database Syst Rev. 2022 Jul 29;7(7):CD011819.[Abstract][Full Text]
47. van Laar JM, Farge D, Sont JK, et al. 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.[Abstract][Full Text]
48. Seo S, Jung HK, Gyawali CP, et al. Treatment response with potassium-competitive acid bockers based on clinical phenotypes of gastroesophageal reflux disease: a systematic literature review and meta-analysis. J Neurogastroenterol Motil. 2024 Jul 30;30(3):259-71.[Abstract][Full Text]
49. Baron M, Bernier P, Côté LF, et al. Screening and therapy for malnutrition and related gastro-intestinal disorders in systemic sclerosis: recommendations of a North American expert panel. Clin Exp Rheumatol. 2010 Mar-Apr;28(2 Suppl 58):S42-6.[Abstract][Full Text]
50. McMahan ZH, Kulkarni S, Chen J, et al. Systemic sclerosis gastrointestinal dysmotility: risk factors, pathophysiology, diagnosis and management. Nat Rev Rheumatol. 2023 Mar;19(3):166-81.[Abstract]
51. Rusu A, Munteanu AC, Arbănași EM, et al. Overview of side-effects of antibacterial fluoroquinolones: new drugs versus old drugs, a step forward in the safety profile? Pharmaceutics. 2023 Mar 1;15(3):804.[Abstract][Full Text]
52. American College of Rheumatology. 2023 American College of Rheumatology (ACR) guideline for the treatment of interstitial lung disease in people with systemic autoimmune rheumatic disease. Aug 2023 [internet publication].[Full Text]
53. Raghu G, Montesi SB, Silver RM, et al. Treatment of systemic sclerosis-associated interstitial lung disease: evidence-based recommendations. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2024 Jan 15;209(2):137-52.[Abstract][Full Text]
54. Fernández-Codina A, Walker KM, Pope JE, et al. Treatment Algorithms for Systemic Sclerosis According to Experts. Arthritis Rheumatol. 2018 Nov;70(11):1820-8.[Abstract][Full Text]
55. Omair MA, Alahmadi A, Johnson SR. Safety and effectiveness of mycophenolate in systemic sclerosis. A systematic review. PLoS One. 2015 May 1;10(5):e0124205.[Abstract][Full Text]
56. Tashkin DP, Roth MD, Clements PJ, 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):708-19.[Abstract]
57. Daoussis D, Melissaropoulos K, Sakellaropoulos G, et al. A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease. Semin Arthritis Rheum. 2017 Apr;46(5):625-31.[Abstract]
58. Barnes H, Holland AE, Westall GP, et al. Cyclophosphamide for connective tissue disease-associated interstitial lung disease. Cochrane Database Syst Rev. 2018 Jan 3;1(1):CD010908.[Abstract][Full Text]
59. Brummaier T, Pohanka E, Studnicka-Benke A, et al. Using cyclophosphamide in inflammatory rheumatic diseases. Eur J Intern Med. 2013 Oct;24(7):590-6.[Abstract]
60. Tzouvelekis A, Bonella F, Spagnolo P. Update on therapeutic management of idiopathic pulmonary fibrosis. Ther Clin Risk Manag. 2015 Mar 3;11:359-70.[Abstract][Full Text]
61. Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019 Jun 27;380(26):2518-28.[Abstract][Full Text]
62. Maher TM, Mayes MD, Kreuter M, et al. Effect of nintedanib on lung function in patients with systemic sclerosis-associated interstitial lung disease: further analyses of a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2021 Apr;73(4):671-6.[Abstract][Full Text]
63. Schachna L, Medsger TA Jr, Dauber JH, et al. Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension. Arthritis Rheum. 2006 Dec;54(12):3954-61.[Abstract][Full Text]
64. Shitrit D, Amital A, Peled N, et al. Lung transplantation in patients with scleroderma: case series, review of the literature, and criteria for transplantation. Clin Transplant. 2009 Mar Apr;23(2):178-83.[Abstract]
65. Woodworth TG, Suliman YA, Li W, et al. Scleroderma renal crisis and renal involvement in systemic sclerosis. Nat Rev Nephrol. 2016 Nov;12(11):678-91.[Abstract]
66. Beckett VL, Donadio JV Jr, Brennan LA Jr, et al. Use of captopril as early therapy for renal scleroderma: a prospective study. Mayo Clin Proc. 1985 Nov;60(11):763-71.[Abstract]
67. Reggiani F, Moroni G, Ponticelli C. Kidney involvement in systemic sclerosis. J Pers Med. 2022 Jul 10;12(7):1123.[Abstract][Full Text]
68. 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.[Abstract]
69. Iudici M, van der Goes MC, Valentini G, et al. Glucocorticoids in systemic sclerosis: weighing the benefits and risks - a systematic review. Clin Exp Rheumatol. 2013 Mar-Apr;31(2 Suppl 76):157-65.[Abstract]
70. Medsger TA, Masi AT, Rodnan GP, et al. Survival with systemic sclerosis: a life-table analysis of clinical and demographic factors in 309 patients. Ann Intern Med. 1971 Sep;75(3):369-76.[Abstract]
71. Helfrich DJ, Banner B, Steen VD, et al. Normotensive renal failure in systemic sclerosis. Arthritis Rheum. 1989 Sep;32(9):1128-34.[Abstract]
72. Tamborrini G, Distler O. Update in pulmonary hypertension associated with connective tissue diseases: a systematic literature review. Dtsche Med Wochenschr [in German]. 2008 Oct;133(suppl 6):S199-S202.[Abstract][Full Text]
73. Kowal-Bielecka O, Avouac J, Pittrow D, et al. Echocardiography as an outcome measure in scleroderma-related pulmonary arterial hypertension: a systematic literature analysis by the EPOSS group. J Rheumatol. 2010 Jan;37(1):105-15.[Abstract]
74. Jing ZC, Yu ZX, Shen JY, et al, Efficacy and safety of Vardenafil in the treatment of pulmonary arterial hypertension (EVALUATION) Study Group. Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2011 Jun 15;183(12):1723-9.[Abstract][Full Text]
75. Avouac J, Wipff J, Kahan A, et al. Effects of oral treatments on exercise capacity in systemic sclerosis related pulmonary arterial hypertension: a meta-analysis of randomised controlled trials. Ann Rheum Dis. 2008 Jun;67(6):808-14.[Abstract]
76. Grünig E. Treatment of pulmonary arterial hypertension in connective tissue disease. Drugs. 2012 May 28;72(8):1039-56.[Abstract]
77. Klinger JR, Elliott CG, Levine DJ, et al. Therapy for Pulmonary Arterial Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report. Chest. 2019 Mar;155(3):565-86.[Abstract][Full Text]
78. Herrick A. Raynaud's phenomenon (secondary). Clinical Evid. 2008 Sep 26;2008:1125.[Abstract][Full Text]
79. O'Donohue WJ. Home oxygen therapy. Clin Chest Med. 1997 Sep;18(3):535-45.[Abstract][Full Text]
80. ClinicalTrials.gov. Study of intravenous ATYR1923 (efzofitimod) for pulmonary sarcoidosis. Jul 2023 [internet publication].[Full Text]
81. ClinicalTrials.gov. Study to evaluate the efficacy, safety, and tolerability of efzofitimod in patients with systemic sclerosis (SSc)-related interstitial lung disease (ILD) (SSc-ILD). May 2025 [internet publication].[Full Text]
82. ClinicalTrials.gov. Efficacy and safety of belumosudil in subjects with diffuse cutaneous systemic sclerosis (dcSSC). Jun 2023 [internet publication].[Full Text]
83. ClinicalTrials.gov. KD025 in subjects with diffuse cutaneous systemic sclerosis. Aug 2023 [internet publication].[Full Text]
84. ClinicalTrials.gov. Dedicated drug-drug interaction (DDI) study in healthy volunteers. ClinicalTrials.gov Identifier: NCT04939467. Oct 2021 [internet publication].[Full Text]
85. Khanna D, Albera C, Fischer A, et al. An open-label, phase II study of the safety and tolerability of pirfenidone in patients with scleroderma-associated interstitial lung disease: the LOTUSS Trial. J Rheumatol. 2016 Sep;43(9):1672-9.[Abstract][Full Text]
86. American College of Rheumatology. 2022 American College of Rheumatology (ACR) guideline for vaccinations in patients with rheumatic and musculoskeletal diseases. Feb 2023 [internet publication].[Full Text]
87. Denton CP, De Lorenzis E, Roblin E, et al. The 2024 British Society for Rheumatology guideline for management of systemic sclerosis. Rheumatology (Oxford). 2024 Nov 1;63(11):2956-75.[Abstract][Full Text]
88. Mayes MD, Lacey JV Jr, Beebe-Dimmer J, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum.2003 Aug;48(8):2246-55.[Abstract]
89. Beretta L, Scorza R, Del Papa N, et al. Bosentan improves functional class, pulmonary artery systolic pressure, and DLCO in scleroderma patients with pulmonary hypertension: a possible synergy with iloprost. J Rheumatol. 2006 Sep;33(9):1915-6.[Abstract]
90. Kaide CG, Khandelwal S. Hyperbaric oxygen: applications in infectious disease. Emerg Med Clin North Am. 2008 May;26(2):571-95.[Abstract]
91. Proudman SM, Stevens WM, Sahhar J, et al. Pulmonary arterial hypertension in systemic sclerosis: the need for early detection and treatment. Intern Med J. 2007 Jul;37(7):485-94.[Abstract]
