Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by vasculopathy and fibrosis of the skin and other organs. Based on the extent of cutaneous involvement, SSc is categorized as limited or diffuse. Limited SSc, which is more common, begins with cutaneous sclerosis of the fingers, hands, and face, which then progresses proximally toward the center of the body. Cutaneous involvement may be followed by internal organ involvement 10–20 years after disease onset. Diffuse SSc, which is less common, may be life-threatening in individuals with early involvement of the heart, lungs, or kidneys. The term CREST syndrome (calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) has historically been used to describe a group of symptoms that are typically present in patients with limited SSc; however, these symptoms may also be seen in patients with diffuse SSc. Treatment is symptomatic and based on the extent of skin and internal organ involvement. A multidisciplinary approach is recommended to address the complex and heterogeneous manifestations of SSc. Scleroderma renal crisis (SRC) is a life-threatening complication of SSc characterized by the abrupt onset of hypertension and oliguric AKI. Management of SRC includes initiation or uptitration of ACE inhibitors and nephrology consultation. Cardiopulmonary complications of SSc are common and require management of the specific condition as well as possible additional immunosuppressive therapy. The prognosis varies depending on organ involvement; pulmonary arterial hypertension (PAH), interstitial lung disease (ILD), and cardiac disease significantly increase the mortality rate.
The pathophysiology of SSc is not completely understood, but several factors play a role in the development of the disease.
- Autoimmunologic component (see “Diagnostics”)
- Inflammatory synthesis of extracellular matrix: fibroblast proliferation and increased synthesis of normal collagen leading to fibrosis
- Noninflammatory vasculopathy: underlying mechanism of many of the more severe disease features, e.g., CAD, pulmonary artery hypertension, and renal crisis
SSc is most commonly described as limited or diffuse based on the cutaneous manifestations and symptom progression. 
|Common SSc subtypes|
|Limited SSc||Diffuse SSc|
|Cutaneous distribution|| || |
|Extracutaneous manifestations |
|Onset of systemic symptoms || || |
- C: Calcinosis cutis: small white calcium deposits on the pressure points of the extremities (e.g., elbows, knees, fingertips)
- E: Esophageal hypomotility (systemic sclerosis): smooth muscle atrophy and fibrosis → esophageal dysmotility and decreased lower esophageal sphincter pressure → dysphagia, gastroesophageal reflux, heartburn → aspiration, Barrett esophagus, stricture
- S: Sclerodactyly
- T: Telangiectasia
- Thickening and hardening of the skin, which appears smooth, shiny, and puffy
- Sclerodactyly: fibrotic thickening and tightening of the skin on the fingers and hands
- Multiple, painful ischemic digital ulcers with atrophy and necrotic spots
- Digital pitting: hyperkeratotic scarring that most commonly affects the fingertips
- Lesions on the proximal nail fold
- Depigmentation with sparing of perifollicular pigmentation (salt-and-pepper appearance)
- Face changes
- Scleroderma renal crisis (SRC): medical emergency, see “Management of SRC.”
- Chronic kidney disease: reduced kidney function due to abnormal collagen deposition → thickening of renal arteriolar walls → decreased renal blood flow
- Cardiovascular 
- Pulmonary 
Other extracutaneous 
- Gastrointestinal tract
- Vascular disease
- Arthralgia and myalgia: may develop into contractures
Consult rheumatology for all patients.
- SSc is a clinical diagnosis.
- Perform a comprehensive evaluation to determine disease severity.
- Obtain routine laboratory studies and SSc-specific evaluations.
- Assess for cardiopulmonary complications (even if asymptomatic).
- Consider additional studies to monitor for organ involvement.
- Classification criteria for SSc can help identify SSc . 
Organ involvement typically occurs early in the course of SSc. 
Scleroderma renal crisis is a medical emergency with a high mortality rate. Promptly evaluate serum creatinine and urine protein in individuals with SSc who present with an acute rise in blood pressure and start . 
Routine evaluations 
Obtain the following studies in all patients with suspected SSc.
- Renal function testing
- Inflammatory markers: ↑ CRP, ↑ ESR
- Antinuclear antibodies (ANA): present in ∼ 90% of patients 
- SSc-specific autoantibodies 
- Anticentromere antibodies: associated with limited SSc, increased risk for vascular complications (e.g., PAH)
- Anti-Scl-70 (anti-topoisomerase I antibody): associated with severe and rapidly progressive diffuse SSc, limited SSc, ILD, digital ulcers
- Anti-RNA polymerase III: associated with diffuse SSc, scleroderma renal crisis
- BNP: to detect cardiopulmonary disease
- : Microvascular abnormalities are observed in ∼ 97% of individuals with SSc. 
Cardiopulmonary assessment: Obtain baseline testing and refer to a specialist for further testing. 
- ECG or Holter monitor: arrhythmia due to fibrosis
- Echocardiogram (TTE): diastolic and/or systolic heart failure, pericardial effusion, pulmonary hypertension
- High-resolution CT (HRCT) chest: findings suggestive of ILD (e.g., reticular opacities, fibrosis)
- Pulmonary function testing: typically ↓ FVC and ↓ DLCO
Consider early diagnostic testing to uncover silent disease.
Additional studies 
Depending on the patient's clinical features and risk factors, consider the following studies:
- Gastrointestinal tract studies (e.g., EGD, gastric emptying study): e.g., to rule out GERD or dysmotility
- serology (associated with PAH) are present : when clinical or positive
- Cardiac MRI: for patients with diffuse SSc (associated with cardiac involvement)
Upper gastrointestinal tract involvement is observed in almost all patients who have had SSc for > 10 years.
Mixed connective tissue disease (MCTD, Sharp syndrome)
- Definition: a syndrome characterized by overlapping symptoms of three autoimmune diseases: systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and polymyositis
- Etiology: unknown
Clinical features: Course is usually milder than that of other connective tissue diseases (CTD) but may progress into another CTD.
- Initial presentation: usually nonspecific symptoms (e.g., fatigue, arthralgia, low-grade fever)
- Characteristic symptoms, usually manifesting over the course of several years, include:
- Less common symptoms include aseptic meningitis, hepatomegaly, and splenomegaly.
- Involves clinical examination, patient history, and serological tests
- Patients are positive for ANAs and anti-U1 RNP (see “ ”).
- Low to moderate doses of corticosteroids (e.g., prednisolone) to treat disease flares
- Immunosuppressants to prevent pulmonary hypertension
- Disease-modifying antirheumatic drugs for rheumatoid arthritis-like polyarthritis
- Proton pump inhibitors for GERD
- Calcium channel blockers (CCBs) for Raynaud phenomenon
- Antimalarials to modify lupus-like disease
- Complications: increased risk of pulmonary hypertension and interstitial lung disease
The differential diagnoses listed here are not exhaustive.
General principles 
- Refer to a specialist early.
- Treatment focuses on organ-specific, symptomatic therapy.
- In diffuse cutaneous disease or severe organ involvement, systemic immunomodulatory medication is indicated.
- Monitor for organ involvement and complications frequently to reduce mortality. 
Cutaneous disease 
- Raynaud phenomenon (RP)
- Digital ulceration (DU)
- Cutaneous fibrosis
- Calcinosis cutis: carbon dioxide laser, or surgical removal of symptomatic lesions
Supportive care 
- Avoid hand trauma and exposure to cold (e.g., by using gloves).
- Prevent dry skin (e.g., with warm oil, paraffin baths, emollients).
- Encourage smoking cessation. 
- Consider vasodilatory physical therapy and lymph drainage.
- Offer antihistamines for treatment of pruritus.
- Avoid beta blockers.
- Chronic kidney disease: See “Management of CKD.”
Manage specific cardiac and/or pulmonary conditions depending on manifestations (see “Clinical features”).
Heart disease: depending on specific manifestation
- See “ .”
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- See “ .”
- See “ .”
- See “Restrictive cardiomyopathy.”
- Pulmonary disease
Screen all patients for as this can signify cardiopulmonary disease.
Gastrointestinal disease 
Management of SRC 
- Clinical suspicion: There are no validated diagnostic criteria.
- Blood pressure management 
Secondary prevention 
- Advise regular blood pressure monitoring (e.g., 3–4 mornings per week) for patients with risk factors for SRC:
- Maintain a low threshold for .
Individuals with diffuse SSc, those receiving glucocorticoids, and/or with anti-RNA polymerase III antibodies are at higher risk for SRC and should be closely monitored (e.g., blood pressure measurement three times a week and urinalysis at regular intervals).