Systemic Sclerosis (SSc)

Systemic sclerosis (SSc) is a rare, chronic autoimmune disorder of connective tissue characterized by the widespread and excessive deposition of collagen in tissues.¹ In addition, microvascular endothelial damage may contribute to internal organ dysfunction and comorbidities.^2,3

The underlying etiology of autoimmunity in SSc is currently unknown and under investigation; however, researchers hypothesize that a combination of genetic susceptibility and environmental exposures triggers immune system dysfunction, vascular endothelial changes, and fibrosis.⁴ 

Endothelial damage may stimulate the release of a cascade of cellular signaling molecules (eg, cytokines, enzymes, and soluble receptors) from fibroblasts, macrophages, T cells, and mast cells. This process leads to changes in extracellular matrix compounds, especially collagen types I, III, V, and VII. An increase in collagen synthesis and the suppression of collagen degradation result in the excessive deposition of collagen in tissues throughout the body.⁴ 

Dermal Dysfunction

Dermal changes in SSc result from the deposition of more compact collagen in the reticular dermis, thinning of the epidermis, atrophy of the dermal appendages, and deterioration of the rete pegs. The accumulation of T cells in the dermis causes significant scarring within subcutaneous and dermal tissues.³ 

The characteristic thickening and hardening of the skin due to fibrosis is a hallmark of this disease, leading to the name of systemic sclerosis (alternatively called systemic scleroderma). Usually, this fibrotic feature is first noticeable in the skin of the fingers and hands.¹

The degree of dermal involvement varies depending on the subtype of SSc. Limited cutaneous scleroderma manifests with isolated skin involvement. Diffuse systemic sclerosis affects both the skin and internal organs.³ In a third, rare type of SSc, systemic sclerosis sine scleroderma, skin involvement is absent and only internal organs are involved.¹

Read more about SSc types 

Joint Dysfunction

In SSc, chronic inflammation and fibrosis of the synovial membranes, articular surfaces, and soft tissues of the joints lead to joint stiffness and pain. Range of motion may decrease as a consequence of pain, swelling, and muscle weakness in affected joints. Over time, contractures may develop as a result of skin tightening around the joints.^3,5

Read more about SSc prognosis

Esophageal and Gastrointestinal Dysfunction

Impairment of esophageal and gastrointestinal motility as a result of fibrosis leads to dysfunction of the lower esophageal sphincter and gastrointestinal reflux disease (GERD), dysphagia, and secondary strictures.^1,3 Degeneration of the intestinal muscularis mucosae results in the formation of pseudodiverticula in the colon and ileum.³  

The pathogenesis of gastrointestinal dysmotility in SSc involves progressive myopathy, neuropathy, and fibrotic changes that alter compliance and contractility of the gastrointestinal tract wall. Other symptoms of gastrointestinal dysmotility include nausea, vomiting, constipation, diarrhea, bloating, small intestinal bacterial overgrowth (SIBO), distension, abdominal pain, fecal incontinence, and (rarely) megacolon. Over time,  malnutrition and mechanical or pseudo-obstruction of the intestines may develop, all of which can be life-threatening.⁶

Read more about SSc complications

Pulmonary Dysfunction

Fibrosis of the lung tissue and bronchioles may cause dyspnea and progress to interstitial lung disease.^3,7 Intimal hyperplasia of the pulmonary arteries may progress to pulmonary hypertension.^1,3

The pathogenesis of interstitial lung disease in SSc involves chronic inflammation, collagen deposition, and epithelial damage in which interleukin-6 (IL-6) is a pivotal mediator. The presence of CXCL4, CCL18, monocytes, and activated macrophages points to immune-mediated tissue damage and response to such injury, evidenced by the presence of transforming growth factor beta (TGF-β). TGF-β plays a role in activating fibroblasts and regulating epithelial tissue repair.⁷

Read more about SSc histology

Cardiac and Vascular Dysfunction

Fibrosis of the cardiac tissues may contribute to conduction system abnormalities, myocardial damage, pericardial disease, and less frequently, valvular disease.^3,8 Pulmonary arterial hypertension, renal disease, and interstitial lung disease also may contribute to the development of cardiac abnormalities.⁸ Small-vessel vasculopathy and endothelial changes promote hypertension and Raynaud phenomenon.^3,8

The combination of fibrotic, ischemic, and inflammatory lesions contributes to recurrent ischemic-reperfusion injury, myocarditis, focal ischemia, and myocardial fibrosis affecting cardiac muscle contractility.⁸  

Read more about SSc clinical features

Renal Dysfunction

Endothelial cell damage causing intimal hyperplasia and proliferation of the renal, arcuate, and intralobular arteries leads to renal ischemia and hypertension. Intimal hyperplasia leads to platelet aggregation, adhesion, and the release of platelet factor; these further contribute to excess collagen deposition, luminal narrowing, reduced perfusion, and renal damage.^3,9

Other pathogenetic factors may also contribute to renal damage in SSc, including autoantibody-related glomerulonephritis, proteinuria, albuminuria, decreased renal filtration, and side effects of drugs.⁹ 

Read more about SSc life expectancy

References

1. Systemic scleroderma. MedlinePlus. Accessed April 15, 2023.
2. Pattanaik D, Brown M, Postlethwaite BC, Postlethwaite AE. Pathogenesis of systemic sclerosis. Front Immunol. 2015;6. doi:10.3389/fimmu.2015.00272
3. Nevares AM. Pathophysiology of systemic sclerosis. Merck Manual Professional Version. Updated October 2022. Accessed April 15, 2023.
4. Schwartz RA. Systemic sclerosis: pathophysiology. Medscape. Updated April 16, 2021. Accessed April 15, 2023.
5. Systemic sclerosis (scleroderma). Versus Arthritis. Accessed April 15, 2023.
6. Shreiner AB, Murray C, Denton C, Khanna D. Gastrointestinal manifestations of systemic sclerosis. J Scleroderma Relat Disord. 2016;1(3):247-256. doi:10.5301/jsrd.5000214
7. Nihtyanova SI, Denton CP. Pathogenesis of systemic sclerosis associated interstitial lung disease. J Scleroderma Relat Disord. 2020;5(2 Suppl):6-16. doi:10.1177/2397198320903867
8. Lambova S. Cardiac manifestations in systemic sclerosis. World J Cardiol. 2014;6(9):993-1005. doi:10.4330/wjc.v6.i9.993
9. Bruni C, Cuomo G, Rossi FW, Praino E, Bellando-Randone S. Kidney involvement in systemic sclerosis: from pathogenesis to treatment. J Scleroderma Relat Disord. 2018;3(1):43-52. doi:10.1177/2397198318758607

Reviewed by Harshi Dhingra, MD, on 4/30/2023.

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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.