Systemic Sclerosis (SSc)

Systemic sclerosis (SSc), also known as scleroderma, is a rare autoimmune disease of connective tissue that causes fibrosis and vascular damage. SSc in various organs and tissues leads to a wide range of symptoms that affect quality of life and, in severe cases, may be life-threatening. The mortality rate for this disease is higher than that of other rheumatic diseases.^1,2

There are 3 types of systemic sclerosis: limited cutaneous SSc, a subtype of which is CREST syndrome; diffuse cutaneous SSc; and SSc without skin involvement.^2,3

Etiology

The exact cause of SSc is not yet fully understood, but genetic and environmental factors are believed to be involved.⁴ Several genes associated with the disease have been identified, including HLA DRB1, IRF5, and STAT4, but no single gene has been found to be responsible for SSc.⁴

Exposure to environmental factors, such as silica, solvents, and organic chemicals, has also been implicated in the development of SSc.⁴

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Pathophysiology

The pathophysiology of SSc is complex and involves autoimmunity, fibrosis, and vascular damage. Vascular damage in SSc is linked to an immune response.^4,5

In the initial phase of the disease, endothelial cell damage leads to vasculopathy and activation of the immune system,^4,5 followed by the production of autoantibodies and the activation of inflammatory cells, such as T cells and B cells. Activated immune cells then release cytokines and growth factors that stimulate fibroblast activation and collagen deposition, resulting in tissue fibrosis.⁴ 

In cases of SSc that affect the vascular system, the microvessels and arterioles are typically involved. Endothelial cell swelling, apoptosis, and modified expression of cytokines and adhesion proteins are followed by hypoxia and vascular damage.⁵

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Signs and Symptoms

The symptoms of systemic sclerosis vary depending on the extent and severity of the disease.^1,2 Raynaud phenomenon is the most common initial symptom, together with swelling of the distal extremities and gradual thickening of the skin of the fingers.^3,4

The hallmark of SSc is skin fibrosis, which can develop on the hands, face, and other parts of the body. Fibrosis can result in tightening and hardening of the skin, which can cause difficulty with movement and lead to contractures.⁴

Other common symptoms include arthralgia and myalgia as well as gastrointestinal symptoms such as heartburn and dysphagia. SSc may also affect the lungs, heart, and kidneys and result in organ failure.⁴

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Diagnosis

The diagnosis of SSc is based on a combination of clinical features and laboratory test results.³ The 2013 European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) have established diagnostic criteria for SSc that can guide the medical team to a definitive diagnosis.^1,3 These include thickening of the skin of the fingers (sclerodactyly), telangiectasia, pitting scars, fingertip lesions, abnormal nail fold capillaries, pulmonary artery hypertension, the presence of antinuclear antibodies, anti–RNA polymerase III, anti–Scl-70, anticentromere, and evidence of internal organ involvement.^1,3

Other tests that may be used to support a diagnosis of SSc include imaging of the lungs and heart and pulmonary function tests.³ 

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Prognosis

The rates of morbidity and mortality in individuals with SSc are high.¹ The prognosis of patients with SSc varies depending on the extent and severity of the disease.³ Overall, the prognosis has improved over time, with 5-year survival rates up to 80%.⁴ However, patients who present with advanced pulmonary arterial hypertension still have a worse prognosis, with 2-year survival rates below 50%.⁴ Interstitial lung disease is now the leading cause of death in patients with SSc.²

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Treatment

Currently, no cure for SSc exists, but treatments are available that can help manage symptoms and slow progression of the disease.⁴

Topical treatments, such as moisturizers and antihistamines, may be used to relieve the symptoms of skin disease. When skin involvement is severe, methotrexate, hydroxychloroquine, and other immunosuppressive medications, such as CellCept® (mycophenolate mofetil) and Cytoxan® (cyclophosphamide), may be used.⁴

To manage Raynaud phenomenon, medications such as calcium channel blockers and phosphodiesterase inhibitors may be prescribed.⁴

Gastrointestinal symptoms can be managed with proton pump inhibitors and motility agents such as Reglan® (metoclopramide). Patients with lung involvement may require immunosuppressive medications such as Cytoxan and CellCept, and oxygen therapy may be needed in cases of severe lung disease. Patients with kidney involvement may require treatment with angiotensin-converting enzyme inhibitors.⁴

In addition to medications, lifestyle modifications can be helpful in managing the symptoms of SSc. Patients with Raynaud phenomenon should be advised to keep warm. Regular exercise can help maintain joint mobility and muscle strength, and physical therapy may be recommended to preserve mobility and function.^3,4 

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References

1. Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017;390(10103):1685-1699. doi:10.1016/S0140-6736(17)30933-9

2. Volkmann ER, Andréasson K, Smith V. Systemic sclerosis. Lancet. 2023;401(10373):304-318. doi: 10.1016/S0140-6736(22)01692-0

3. Systemic sclerosis. MSD Manual Professional Version. Revised October 2022. Accessed April 8, 2023.

4. Adigun R, Goyal A, Hariz A. Systemic sclerosis. StatPearls [Internet]. Updated May 8, 2022. Accessed April 8, 2023.

5. Rosendahl AH, Schönborn K, Krieg T. Pathophysiology of systemic sclerosis (scleroderma). Kaohsiung J Med Sci. 2022;38(3):187-195. doi:10.1002/kjm2.12505

Reviewed by Debjyoti Talukdar, MD, on 4/20/2023.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.