Systemic Sclerosis (SSc)

Systemic sclerosis (SSc) is a rare, chronic, autoimmune-mediated disorder of connective tissue in which widespread fibrosis and vasculopathy affect multiple organs and organ systems, including the skin, lungs, kidneys, heart, digestive system, and musculoskeletal system. The prevalence of certain comorbidities is increased among people with SSc.¹ 

Autoimmune Comorbidities

Some comorbidities are related to underlying autoimmune activity in SSc. Individuals with one autoimmune condition are at increased risk for the development of another.² 

People with SSc and comorbid autoimmune conditions may have what is called scleroderma overlap syndrome.³ Overlap syndrome can also be categorized as a rare subtype of SSc along with limited cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis, and systemic sclerosis sine scleroderma.⁴

Read more about SSc disease types

Scleroderma Overlap Syndrome

Overlap syndrome is a condition in which at least 2 connective tissue diseases (CTDs) are present in the same individual. These CTDs may include³: 

• Systemic sclerosis
• Dermatomyositis or polymyositis
• Sjögren syndrome
• Rheumatoid arthritis 
• Systemic lupus erythematosus

Vasculitis has also been mentioned as a potential comorbidity in patients who have SSc with overlap syndrome.⁴ The simultaneous occurrence of SSc and another autoimmune condition exacerbates progression of the disease-related comorbidity and worsens the prognosis.³

Studies on Overlap Syndrome

Researchers in Israel conducted a systematic review of the literature published between 1977 and 2009. They analyzed the medical records of 165 patients who had SSc to determine the frequency of SSc overlap with other autoimmune conditions.³ Of the 165 patients, 40 met the criteria for scleroderma overlap syndrome. Comorbid SSc and dermatomyositis or polymyositis were present in approximately 47.5% of these patients, comorbid SSc and Sjögren syndrome in 42.5%, comorbid SSc and rheumatoid arthritis in 15.4%, and comorbid SSc and systemic lupus erythematosus in 5%.³

Another study indicated that several other autoimmune conditions were also more likely to develop in individuals with SSc, including inflammatory bowel disease and multiple sclerosis, than in persons without SSc.⁵

Read more about SSc clinical features

Disease-Related Comorbidities/Complications

Other comorbidities are directly related to the progression of fibrosis and vasculopathy in SSc. These develop as SSc begins to affect certain internal organs.

Pulmonary Arterial Hypertension/Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) occurs more often in limited cutaneous SSc but may also be seen in other SSc subtypes. The prevalence of PAH among people with SSc is estimated to be 5% to 15%.⁶ 

The etiology of SSc-related PAH is unclear. Inflammation, endothelial injury, and possibly intraluminal microthrombosis have been suggested as pathogenic pathways to the remodeling of precapillary arterioles and pulmonary arteries. These processes lead to progressive peripheral vascular resistance, increased pulmonary arterial pressure, and eventually right ventricular decompensation and failure.⁶

Other forms of pulmonary hypertension related to SSc disease mechanisms include pulmonary hypertension associated with left-sided heart disease, interstitial lung disease (ILD), chronic thromboembolism, and pulmonary venous occlusive disease. Valvular disease and/or systolic or diastolic myocardial dysfunction may cause pulmonary hypertension due to left-sided heart disease. Chronic hypoxia secondary to advanced ILD may also cause pulmonary hypertension.⁶

Read more about SSc etiology

Interstitial Lung Disease

Interstitial lung disease develops in 35% to 52% of people with SSc and accounts for 20% to 40% of cases of SSc-related mortality. SSc-associated ILD is more likely to occur in males, Black individuals, and persons with diffuse cutaneous SSc, cardiac involvement, or anti-Scl70 or anti-topoisomerase I autoantibodies.⁷

The pathogenesis of SSc-associated ILD is not fully understood; however, it is known that endothelial cell, vascular, and alveolar epithelial cell injury all precede the onset of pulmonary fibrosis. Thrombin, transforming growth factor beta (TGF-β), and the Wnt-β/catenin signaling pathway are all believed to mediate the development of SSc-associated ILD.⁸

Read more about SSc complications

Scleroderma Renal Crisis

Scleroderma renal crisis can occur following an abrupt elevation of blood pressure; severe hypertension then drives the development of progressive renal failure, hypertensive encephalopathy, congestive heart failure, and/or microangiopathic hemolytic anemia.⁹ 

The prevalence of scleroderma renal crisis in patients with SSc has decreased from 20% in the older literature to 5% to 10% at present. Scleroderma renal crisis is more common in individuals with diffuse cutaneous SSc (10% to 25%) than in people with limited cutaneous SSc (1% to 2%).⁹

The pathogenesis of scleroderma renal crisis is not well understood; however, initial injury to endothelial cells induces structural changes within the vasculature, including intimal thickening, proliferation, and fibrin deposition. As a result, circulation to the kidneys is reduced and may be further reduced by vasospasm due to Raynaud phenomenon, with the development of renal ischemia and hyperplasia of the juxtaglomerular apparatus. Activation of the renin-angiotensin-aldosterone system (RAAS) then results in a steep rise in blood pressure that exacerbates the injury to the renal vasculature. The cycle of injury and RAAS activation continues, causing malignant hypertension and renal crisis.⁹

Renal crisis may escalate to end-stage renal disease in people with SSc.¹⁰

Read more about SSc prognosis

Increased Risk for Certain Comorbidities

Individuals with SSc are at increased risk for the following comorbidities:

• Cardiovascular conditions,¹¹ such as dyslipidemia¹² and acute myocardial infarction¹³
• Malignancies^11,14
• Infections^11,15
• Psychological disorders, such as depression, which is closely interrelated with decreased gastrointestinal function and disability^11,16
• Thyroid disease¹⁷

Increased Risk of Cardiovascular Disease

People with SSc have abnormal lipid profiles and are at increased risk for cardiovascular diseases in comparison with controls. Skin thickness is independently and inversely correlated with cholesterol efflux capacity in this patient population.¹²

In one study, SSc independently increased the risk for acute myocardial infarction (hazard ratio of 2.45). Immunosuppression did not decrease risk for acute myocardial infarction in this patient population.¹³  

Increased Risk of Malignancies

Widespread fibrosis, chronic inflammation, B-cell stimulation, environmental exposure to substances like silica, genetic predisposition, autoantibody activity, and oxidative stress and damage to DNA may explain the predisposition of individuals with SSc to the development of cancer. Additionally, older age at the onset of SSc increases the risk for malignancy.¹⁴

Increased Risk of Infection

The increased risk of infection is partly due to SSc itself. ILD is associated with a greater likelihood of acquiring a respiratory infection; digital ulceration and calcinosis increase the risk of skin infection and possibly even osteomyelitis. Secondarily, treatment with immunomodulation and immunosuppression to treat the autoimmunity that causes SSc also predisposes people with SSc to infections, especially opportunistic infections that their weakened immune system cannot overcome.¹⁵

Increased Risk of Depression and Associated Gastrointestinal Disorders

The incidence of depression in people with SSc is correlated with decreased functional status along with poor gastrointestinal function.¹⁶ Gastrointestinal reflux, esophageal dysmotility, small-intestinal bacterial overgrowth, and pseudo-obstruction are gastrointestinal comorbidities that occur frequently in individuals with SSc.¹⁸

Increased Risk of Thyroid Disease

Researchers in India reported that thyroid disease, particularly hypothyroidism, was the most common comorbidity in patients with SSc, occurring in 17.78% of them according to the Indian Rheumatology Association database.¹⁷

Read more about SSc risk factors

References

1. Nevares AM. Systemic sclerosis (scleroderma). Merck Manual Professional Version. Updated October 2022. Accessed April 28, 2023.
2. Overlapping autoimmune diseases. The Myositis Association. Accessed April 28, 2023.
3. Balbir-Gurman A, Braun-Moscovici Y. Scleroderma overlap syndrome. Isr Med Assoc J. 2011;13(1):14-20. 
4. Systemic sclerosis subtypes. UpToDate. Accessed April 28, 2023.
5. Robinson D, Eisenberg D, Nietert PJ, et al. Systemic sclerosis prevalence and comorbidities in the US, 2001–2002. Curr Med Res Opin. 2008;24(4):1157-1166. doi:10.1185/030079908X280617
6. Naranjo M, Hassoun PM. Systemic sclerosis-associated pulmonary hypertension: spectrum and impact. Diagnostics (Basel). 2021;11(5):911. doi:10.3390/diagnostics11050911
7. Rahaghi FF, Hsu VM, Kaner RJ, et al. Expert consensus on the management of systemic sclerosis-associated interstitial lung disease. Respir Res. 2023;24:6. doi:10.1186/s12931-022-02292-3
8. Schoenfeld SR, Castelino FV. Interstitial lung disease in scleroderma. Rheum Dis Clin North Am. 2015;41(2):237-248. doi:10.1016/j.rdc.2014.12.005
9. Vaidya PN, Basyal B, Finnigan NA. Scleroderma and renal crisis. StatPearls [Internet]. Updated January 22, 2023. Accessed April 28, 2023.
10. Lavergne A, Pladys A, Couchoud C, Lassalle M, Vigneau C. Systemic sclerosis and end-stage renal disease: study of patient characteristics, follow-up and outcomes in France. J Nephrol. 2021;34(2):617-625. doi:10.1007/s40620-020-00746-9
11. Pagkopoulou E, Arvanitaki A, Daoussis D, Garyfallos A, Kitas G, Dimitroulas T. Comorbidity burden in systemic sclerosis: beyond disease-specific complications. Rheumatol Int. 2019;39(9):1507-1517. doi:10.1007/s00296-019-04371-z
12. Ferraz-Amaro I, Delgado-Frías E, Hernández-Hernández V, et al. HDL cholesterol efflux capacity and lipid profile in patients with systemic sclerosis. Arthritis Res Ther. 2021;23:62. doi:10.1186/s13075-021-02443-9
13. Chu SY, Chen YJ, Liu CJ, et al. Increased risk of acute myocardial infarction in systemic sclerosis: a nationwide population-based study. Am J Med. 2013;126(11):982-988. doi:10.1016/j.amjmed.2013.06.025
14. Zeineddine N, Khoury LE, Mosak J. Systemic sclerosis and malignancy: a review of current data. J Clin Med Res. 2016;8(9):625-632. doi:10.14740/jocmr2606w
15. Barahona-Correa JE, De la Hoz A, López MJ, Garzón J, Allanore Y, Quintana-López G. Infections and systemic sclerosis: an emerging challenge. Revista Colombiana de Reumatología (English Edition). 2020;27:62-84. doi:10.1016/j.rcreue.2019.12.004
16. Nietert PJ, Mitchell HC, Bolster MB, Curran MY, Tilley BC, Silver RM. Correlates of depression, including overall and gastrointestinal functional status, among patients with systemic sclerosis. J Rheumatol. 2005;32(1):51-57. 
17. Chandrashekara S, Shenoy P, Kumar U, Pandya S, Ghosh A. Burden of associated comorbidities in autoimmune rheumatic diseases in Indian population: an interim report based on the Indian Rheumatology Association database. Indian J Rheumatol. 2022;17(3):227-233. doi:10.4103/injr.injr_125_21
18. Miller JB, Gandhi N, Clarke J, McMahan Z. Gastrointestinal involvement in systemic sclerosis. J Clin Rheumatol. 2018;24(6):328-337. doi:10.1097/RHU.0000000000000626

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.