Systemic Sclerosis (SSc)

Systemic sclerosis (SSc) is a heterogeneous disorder whose pathogenesis is characterized by 3 features: small-vessel vasculopathy, autoantibody production, and dysfunction of fibroblasts resulting in increased deposition of extracellular matrix. The clinical signs and symptoms and the prognosis of SSc are variable, with skin thickening and internal organ involvement noted in many patients. Various types of SSc include limited cutaneous SSc, diffuse cutaneous SSc, and SSc without skin involvement.¹ 

ACR-EULAR Classification Criteria

To improve the sensitivity and specificity of the 1980 criteria and reflect advancements in the knowledge of SSc, the American College of Rheumatology and European League Against Rheumatism (ACR-EULAR) created a joint proposal for new classification criteria in 2013. The objectives were to create criteria that (1) encompass a wider range of cases of SSc, including patients in both early and late stages of the disease process; (2) include vascular, immunologic, and fibrotic manifestations; (3) are practical to use in routine clinical practice; and (4) are consistent with the criteria currently used for diagnosing SSc in clinical practice. Rheumatologists, researchers, national and international drug authorities, pharmaceutical companies, and others interested in SSc studies can use these criteria for diagnosis.¹

The ACR-EULAR classification criteria established that SSc can be diagnosed if thickening of the skin of the fingers extends proximal to the metacarpophalangeal joints. 

Absent this finding, the presence of the following 7 features should be noted and scored: thickening of the skin of the fingers, lesions on the fingertips, telangiectasia, abnormal nail fold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud phenomenon, and SSc-related autoantibodies. Patients with a minimum score of 9 are classified with definite SSc.^1,2 

ACR-EULAR Criteria for the Classification of Systemic Sclerosis³  

	Classify a patient as having systemic sclerosis if the sum of points for the criteria below is ≥9.
	Criterion	Points
	Skin thickened on the fingers of both hands, extending proximal to the metacarpophalangeal joints	9
1	Skin on fingers thickened (count only the highest score) Puffy fingers Sclerodactyly	2 4
2	Lesions on fingertips (count only the highest score) Ulcers on tip of digits Pitting scars on fingertips	2 3
3	Telangiectasia	2
4	Abnormal nail fold capillaries	2
5	Pulmonary arterial hypertension and/or interstitial lung disease (maximum score is 2) Pulmonary arterial hypertension Interstitial lung disease	2 2
6	Raynaud phenomenon	3
7	Presence of ≥1 of the following: Centromere antibody Scl-70 antibody RNA polymerase III antibody	3

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Treatment Guidelines

No conclusive therapy or widely recognized disease-modifying agent can change the course of SSc. However, outcomes can be improved with an early diagnosis. The effectiveness of treatment depends on the clinical assessment, identification of the affected organ(s), and progression of the disease. Additionally, it is critical that the objectives of treatment be comprehensive and designed to improve the patient’s quality of life and halt further organ damage. Every person with SSc should be educated about the condition, engage in regular exercise, maintain a healthy diet and lifestyle, and receive emotional support.⁴

Some commonly used immunosuppressive agents in the treatment of SSc include: methotrexate for skin disease, inflammatory arthritis, and myositis; CellCept® (mycophenolate mofetil) for both skin and lung disease; Cytoxan® (cyclophosphamide) for both skin and lung disease; Imuran® (azathioprine) for skin disease, lung disease, and myositis; and Plaquenil® (hydroxychloroquine) for skin disease.⁴ 

Corticosteroids should generally be avoided in SSc. The use of high doses of corticosteroids as well as the prolonged use of low or moderate doses has been linked to scleroderma renal crisis (SRC). If absolutely necessary, such as in cases of active inflammatory alveolitis, refractory inflammatory arthritis, or inflammatory myositis, corticosteroids should be administered in the smallest possible dose for the shortest possible time.⁴

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Organ-Based Guidelines for Therapies

Raynaud Phenomenon and Digital Ulcers

Raynaud phenomenon is an exaggerated response of blood vessels to emotional stress or cold temperatures that manifests as clearly demarcated changes in the color of the skin of digits. Ischemia and ulceration further worsen the condition. Therapy should be aimed at improving quality of life and preventing tissue loss due to ulceration and gangrene.⁵

Recommendations for Raynaud Phenomenon

• Calcium channel blockers and angiotensin II receptor antagonists are the first-line treatments.⁶ 
• The incidence and severity of attacks of Raynaud phenomenon in SSc are lessened by treatment with phosphodiesterase type 5 (PDE-5) inhibitors, according to a meta-analysis of randomized controlled trials. Thus, they should also be considered.⁷ 
• Other treatments that can be considered include selective serotonin reuptake inhibitors, statins, and alpha blockers.⁶ 
• In severe, refractory cases of Raynaud phenomenon associated with SSc, intravenous prostanoid therapy such as with Ventavis® (iloprost) and digital (palmar) sympathectomy with or without injections of Botox® (botulinum toxin) can be considered.⁶ 

Recommendations for Digital Ulcers

• A multidisciplinary team must manage digital ulcers in an integrated manner with both systemic and local treatments.⁶
• Oral vasodilators, analgesics, and required interventions for any infections are the recommended treatments for digital ulcers.⁶
• It is preferred that Revatio® (sildenafil) be used before either intravenous prostanoid therapy or treatment with Tracleer® (bosentan) is considered.⁶ 
• Patients with severe, active digital ulcers should receive intravenous prostanoid therapy. For recurrent, refractory digital ulcers, a phosphodiesterase type 5 inhibitor or intravenous prostanoid therapy and an endothelin receptor antagonist (including bosentan) should be considered.⁶ 
• In severe, refractory cases, clinicians may consider digital (palmar) sympathectomy with or without Botox injections.⁶ 

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SSc-Related Lung Disease

Interstitial lung disease can develop in up to 80% of patients with SSc. It may be mild and stable, but if it is extensive or progressive, immunosuppression should be considered. Lung involvement can take the form of interstitial pneumonitis, bronchiolitis, or pulmonary vascular disease. Lung involvement can be a significant cause of morbidity and mortality in SSc.⁵

Recommendations for Lung Fibrosis

• Every patient with SSc should be evaluated for lung fibrosis. The extent and severity of disease and the likelihood of progression determine the course of treatment.⁶
• Cytoxan by intravenous infusion is the recommended therapy. CellCept may be used as an alternative therapy or after treatment with Cytoxan.⁶  

Recommendations for Pulmonary Arterial Hypertension

• A diagnosis of pulmonary arterial hypertension (PAH) should be based on the results of a comprehensive evaluation, including right-sided heart catheterization and an assessment for any concurrent cardiac or pulmonary disease linked to SSc.⁶
• To treat SSc-related PAH, endothelin receptor antagonists, such as Letairis® (ambrisentan), Tracleer® (bosentan), and Opsumit® (macitentan), phosphodiesterase type 5 inhibitors, or Adempas® (riociguat) should be considered.⁷
• The continuous intravenous administration of epoprostenol (sold as Flolan® and Veletri®) increases functional class, exercise capacity, and hemodynamic measurements. Patients with severe SSc-related PAH should be treated with intravenous epoprostenol.⁷

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Scleroderma Renal Crisis

SRC occurs 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. Close monitoring of a patient with SSc is required to detect any progression to SRC during the first 4 to 5 years. The optimal anthypertensive treatment recommended for SRC is an angiotensin-converting enzyme (ACE) inhibitor such as Capoten® (captopril), which is preferred over enalapril or ramipril.⁵ 

Recommendations for Renal Crisis

• The patient’s blood pressure should be checked at least once a week; close monitoring is required for patients at risk for SRC.⁶
• In many cohort studies, ACE improved survival in patients with SRC. Specialists advise administering ACE inhibitors immediately to manage SRC.⁷ 
• A number of retrospective studies have indicated that glucocorticoids raise the risk of SRC. The blood pressure and renal function of patients with SS who are receiving glucocorticoids should be closely monitored.⁷ 

Read more about SSc risk factors

SSc-Related Gastrointestinal Disease

The gastrointestinal (GI) tract is frequently affected in SSc, and any or all parts, from mouth to anus, may be involved. GI manifestations in SSc include gastrointestinal reflux disease (GERD), delayed gastric emptying, delayed motility leading to postprandial bloating and small-intestinal bacterial overgrowth, chronic constipation, and vascular complications such as gastric antral vascular ectasia. The goal of treatment, which is primarily supportive, is to reduce symptoms.⁵

Recommendations for Gastrointestinal Manifestations

• Proton pump inhibitors should be used to treat SSc-related GI reflux and prevent esophageal strictures and ulcers.⁷
• Prokinetic medications such as Motilium® (domperidone), Reglan® (metoclopramide), and Propulsid® (cisapride) should be administered to manage SSc-related motility issues such as dysphagia, GERD, early satiety, bloating, and pseudo-obstruction. Conservative measures such as sitting in an upright position to facilitate bolus transmit, and avoid recumbency for at least 4 hours following meal consumption are also advised.^5,7 
• The intermittent or rotating use of antibiotics is recommended for the treatment of symptomatic small-intestinal bacterial overgrowth.⁷ 
• Parenteral nutrition should be considered for individuals with substantial weight loss that is resistant to enteral supplementation.⁶
• For the symptomatic therapy of diarrhea or constipation, which frequently alternate, antidiarrheal medications such as Imodium® (loperamide) or laxatives may be used.⁶ 

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Use of Hematopoietic Stem Cell Transplant in SSc

Hematopoietic stem cell transplant (HSCT) should be a treatment option only for carefully selected patients with rapidly progressing SSc who are at risk for organ failure. The careful identification of patients with SSc for whom this type of treatment is appropriate and a skilled medical team are of the utmost importance because HSCT carries a significant risk of treatment-related side effects and early mortality.⁷

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References

1. van den Hoogen F, Khanna D, Fransen J, et al. Classification criteria for systemic sclerosis: an ACR/EULAR collaborative initiative. Arthritis Rheum. 2013;65(11):2737-2747. doi:10.1002/art.38098
2. Scleroderma/systemic sclerosis (2013 EULAR/ACR criteria). Medscape. Accessed May 1, 2023.
3. Systemic sclerosis: laboratory markers for diagnosis and prognosis. Quest Diagnostics. Reviewed July 2021. Accessed May 1, 2023. 
4. Adigun R, Goyal A, Hariz A. Systemic sclerosis. StatPearls [Internet]. Updated May 8 2022. Accessed May 1, 2023.
5. Midhuna PV, Thappa DM. Simplified guidelines for the management of systemic sclerosis. CosmoDerma. 2021;1:24. doi:10.25259/CSDM_12_2021
6. Denton CP, Hughes M, Gak N, et al. BSR and BHPR guideline for the treatment of systemic sclerosis. Rheumatology (Oxford). 2016;55(10):1906-1910. doi:10.1093/rheumatology/kew224
7. Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76(8):1327-1339. doi:10.1136/annrheumdis-2016-209909

Reviewed by Debjyoti Talukdar, MD, on 5/4/2023.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.