Systemic Sclerosis (SSc)

Systemic sclerosis (SSc) is a rare, chronic autoimmune condition characterized by widespread fibrosis and vascular changes affecting the skin and internal organs.¹ Within medical literature, there is a long history of disease presentation, along with continual progress toward refined knowledge that benefits diagnosis and treatment.

Possible SSc in Ancient Writings

Physicians in ancient times, including Hippocrates (460 to 370 BC), Oribasias (325 to 403 AD), and Paulus Agineta (625 to 690 AD), described the thickening of skin and other characteristic symptoms of SSc when reporting on particular cases, although not every characteristic these providers described necessarily reflected individuals with SSc.²

First Modern Description of SSc in the Medical Literature

Carlo Curzio, an Italian physician from Naples, first described the condition in detail (although no term for skin fibrosis existed at the time) in 1753.^1,2 He treated a 17-year-old girl who had symptoms of skin hardening, tightness around the mouth, hardness around the neck, and coolness of the skin. He reported that her skin was “hard, woodlike, and almost leathery, like dry hide.”² 

Curzio treated the patient with warm milk and vapor baths, bleeding from the foot, and small doses of quicksilver, which relieved her symptoms.² Physicians in modern times have debated whether her condition was actually a case of scleroderma or one of Buschke scleroedema.^1,3 

Development of Scleroderma Terminology

In 1836, Giovambattista Fantonetti, an Italian physician from Milan, first used the term scleroderma generale to describe the skin hardening and dry, leathery texture that resulted in tightness and reduced joint range of motion.^1,2 

Advancing Understanding of SSc

Literature Relating to Digital Vascular Disease

In his 1862 doctoral thesis, Maurice Raynaud described triphasic skin changes related to vasospasm, a condition now known as Raynaud phenomenon.^1,4 He reported a series of symptoms in which intermittent pallor and cyanosis due to vasoconstriction were followed by a return to redness and color as normal blood flow resumed.^1,4,5 

Raynaud phenomenon in patients with scleroderma is associated with digital pitting, digital ulcers, and loss of fingertip tissue. These ischemic lesions are more prone to developing infections. Severe or prolonged vasoconstriction may result in dry gangrene, in which a lack of perfusion causes the death of soft tissue.^1,4,5

For a diagnosis of Raynaud phenomenon, vasospasm must occur in the absence of any known vascular disease. However, Raynaud was not aware that the vasospasm he described could precede or be the initial symptom of a general disease. Therefore, Raynaud phenomenon is now classified as primary or secondary.⁴

Read more about SSc clinical features

Literature Relating to Systemic Organ Involvement

Later, in 1894, William Osler, a Canadian physician and the founder of Johns Hopkins Hospital, published The Principles and Practice of Medicine. In this text, Osler described the systemic nature of SSc, citing the pulmonary and/or renal manifestations that accompanied the widespread skin changes. He reported that mortality was frequently increased among individuals with SSc that affected the lungs and/or kidneys.^1,6 

Read more about SSc comorbidities

Emerging Classification of SSc Subtypes

Literature Relating to CREST

In 1910, George Thibierge, a dermatologist, and Raymond Weissenbach, a rheumatologist, coworkers at the dermatological center at the Hôpital Saint-Louis in Paris, presented an interesting case report at the first session of the Hospital Medical Society.^7,8 They described a patient who had progressive SSc associated with Raynaud phenomenon, telangiectasia of the face and torso, and recurrent cutaneous calcinosis.⁷ During the next several years, they reported on repeated subcutaneous calcifications in patients with scleroderma, suggesting a causal link.⁸ 

First called Thibierge-Weissenbach syndrome, the condition these physicians described was renamed CREST syndrome in 1964 by R. H. Winterbauer, an American physician. Winterbauer described a series of 8 patients, each with calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST). However, because Winterbauer only observed esophageal dysmotility in half of the 8 patients, he did not include it in his original report. ^1,9,10 Frayha and colleagues added esophageal dysmotility as a feature of CREST syndrome in 1973, and its inclusion was confirmed by Velayos and colleagues in 1979.^10-12 

It was later discovered that approximately 50% of patients with CREST syndrome express anti-centromere autoantibodies, and these patients have better prognosis than do those with diffuse SSc,⁷ which is more likely to be associated with anti-topoisomerase (20% to 30%) or anti-RNA polymerase III (20%) autoantibodies.⁷ 

Read more about SSc prognosis

Development of SSc Criteria and Classification

In 1980, the American College of Rheumatology (ACR) first attempted to formulate criteria for distinct types of SSc. It examined clinical features and attempted to divide cases by the amount of cutaneous and visceral involvement. However, they realized that more studies needed to be done and left their consensus open to update.¹³ In 1988, LeRoy et al. established the two main subtypes of limited SSc and diffuse SSc.¹⁴ 

In 2013, a joint committee of the ACR and the European League Against Rheumatism (EULAR) developed new classification criteria for SSc, including the subtypes of limited cutaneous SSc, diffuse cutaneous SSc, and SSc without skin involvement.¹⁵ The current classification of CREST is still debated, as some view it as a subtype of limited cutaneous SSc, while others see it as an entity that can overlap with both types of SSc.¹⁶

Read more about SSc types

References

1. Adigun R, Goyal A, Hariz A. Systemic sclerosis. StatPearls [Internet]. Updated May 8, 2022. Accessed April 25, 2023. 
2. Smith Y. Scleroderma history. News Medical Life Sciences. Accessed April 25, 2023.
3. Capusan I. Curzio’s case of scleroderma. Ann Intern Med. 1972;76(1):146. doi:10.7326/0003-4819-76-1-146_2
4. Kaiser H. Maurice Raynaud (1834-1881) and the syndrome named after him. [Article in German.] Z Rheumatol. 2011;70(7):620-624. doi:10.1007/s00393-011-0849-8
5. Raynaud’s phenomenon. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Published April 10, 2017. Accessed April 25, 2023.
6. Biographical overview: William Osler. National Library of Medicine Profiles in Science. Published March 13, 2019. Accessed April 25, 2023. 
7. Meyer O. From Thibierge-Weissenbach syndrome (1910) to anti-centromere antibodies (1980). Clinical and biological features of scleroderma. [Article in French.] Ann Med Interne (Paris). 1999;150(1):47-52.
8. Kaiser H. A dermatologist and a rheumatologist define a syndrome. George Thibierge (1856-1926), Raymond J. Weissenbach (1885-1963). [Article in German.] Z Rheumatol. 2009;68(7):594-598, 600-601. doi:10.1007/s00393-009-0471-1
9. Winterbauer RH. Multiple telangiectasia, Raynaud’s phenomenon, sclerodactyly, and subcutaneous calcinosis: a syndrome mimicking hereditary hemorrhagic telangiectasia. Bull Johns Hopkins Hosp. 1964;114:361-383. 
10. Yoon Jeanie C. CREST syndrome: background. Medscape. Updated October 5, 2020. Accessed April 25, 2023.
11. Frayha RA, Scarola JA, Hulman LE. Calcinosis in scleroderma: a reevaluation of the CREST syndrome [abstract]. Arthritis Rheum. 1973;16:542.
12. Velayos EE, Masi AT, Stevens MB, Shulman LE. The “CREST” syndrome. Comparison with systemic sclerosis (scleroderma). Arch Intern Med. 1979;139(11):1240-1244. doi:10.1001/archinte.1979.03630480030012
13. Masi, AT. Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum. 1980;23:581-590. doi.org/10.1002/art.1780230510
14. LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15(2):202–205.
15. 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;72(11):1747-1755. doi:10.1136/annrheumdis-2013-204424
16. Bobeica C, Niculet E, Craescu M, et al. CREST syndrome in systemic sclerosis patients – is dystrophic calcinosis a key element to a positive diagnosis? J Inflamm Res. 2022;15:3387-3394. doi:10.2147/JIR.S361667

Reviewed by Debjyoti Talukdar, MD, on 4/28/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.