Systemic sclerosis

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.

• ♀ > ♂ (∼ 5:1) ^[1][2]
• Higher incidence in African Americans ^[1]
• Peak incidence: 30–50 years ^[3]

Epidemiological data refers to the US, unless otherwise specified.

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

References:^[4]

Overview ^[5][6]

SSc is most commonly described as limited or diffuse based on the cutaneous manifestations and symptom progression. ^[7]

CREST syndrome

CREST syndrome refers to a constellation of symptoms traditionally associated with limited SSc (can also be seen in diffuse SSc).

• C: Calcinosis cutis: small white calcium deposits on the pressure points of the extremities (e.g., elbows, knees, fingertips)
• R: Raynaud phenomenon
• 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

Cutaneous ^[5]

• 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
  • Edema followed by fibrosis that results in a waxy appearance of the skin
  • Limited range of motion and possibly flexure contractures and clawing of the digits
  • Red-blue discoloration of the fingers
• 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
  • Loss of expression (mask-like facies)
  • Smoothing of deep wrinkles
  • Microstomia (a disproportionately small mouth) accompanied by characteristic perioral wrinkles
  • Shortened frenulum

Renal

• Scleroderma renal crisis (SRC): medical emergency, see “Management of SRC.”
  • Presents in 10–15% of individuals with diffuse SSc and 1–2% of individuals with limited SSc
  • Clinical features of SRC
    • Oliguric acute kidney injury, proteinuria, hematuria
    • Hypertension with or without symptoms of hypertensive emergency
    • Microangiopathic hemolytic anemia (MAHA) and thrombocytopenia
  • Treatment: ACE inhibitors
• Chronic kidney disease: reduced kidney function due to abnormal collagen deposition → thickening of renal arteriolar walls → decreased renal blood flow

Cardiopulmonary ^{[8][9][10][11]}

The heart and lungs are commonly affected by SSc, but usually remain asymptomatic in the early stages of the disease. Overt cardiopulmonary symptoms are associated with poor outcomes. ^[12][13]

• Cardiovascular ^[10][11]
  • Primary cardiac involvement
    • Endomyocardial fibrosis
    • Myocarditis
    • Pericarditis
    • Conduction disease and arrhythmias, e.g., Afib
    • HFpEF
    • Pericardial effusion
  • Secondary involvement: due to PAH, renal failure, amyloidosis
• Pulmonary ^[9]
  • Interstitial lung disease
  • Pulmonary artery hypertension
  • Other: ARDS, diffuse alveolar hemorrhage, aspiration pneumonitis

Other extracutaneous ^[5]

• Gastrointestinal tract
  • Esophageal dysmotility → dysphagia and reflux
  • Small bowel dysmotility → bloating, gas, constipation, and cramping
• Vascular disease
  • Raynaud phenomenon
  • Thromboembolism
  • Erectile dysfunction
• Arthralgia and myalgia: may develop into contractures
• Other
  • Fatigue, weakness, pain
  • Weight loss ^[14]
  • Sicca syndrome, hypothyroidism
  • Increased risk of cancer and adverse fetal outcomes

Approach ^[6][8]

Consult rheumatology for all patients.

• SSc is a clinical diagnosis.
  • Skin thickening on both hands that extends proximal to the MCP joints is diagnostic.
  • Multiple organ system involvement is a hallmark.
• 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 . ^[15]

Organ involvement typically occurs early in the course of SSc. ^[8]

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 management of SRC. ^[14]

Routine evaluations ^[6][8][14]

Obtain the following studies in all patients with suspected SSc.

• Laboratory studies
  • Renal function testing
    • ↑ Serum creatinine
    • Electrolyte disturbances
    • ↑ Spot urine protein/creatinine ratio in SRC
  • Inflammatory markers: ↑ CRP, ↑ ESR
  • Antinuclear antibodies (ANA): present in ∼ 90% of patients ^[6]
  • SSc-specific autoantibodies ^[8][14]
    • 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
• Nailfold capillaroscopy: Microvascular abnormalities are observed in ∼ 97% of individuals with SSc. ^[16]
• Cardiopulmonary assessment: Obtain baseline testing and refer to a specialist for further testing. ^[6][8]
  • 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 ^[6][8]

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
• Right heart catheterization: when clinical features of PH or anticentromere antibody positive serology (associated with PAH) are present
• 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
• Epidemiology
  • Peak onset during the fourth decade of life ^[17]
  • Estimated prevalence is 3.8:100,000 ^[17]
  • ♀ > ♂ (3:1) ^[17]
• 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:
    • Raynaud phenomenon (∼ 90% of patients) ^[17]
    • Polyarthralgia, arthritis
    • Acrosclerosis, synovitis, and overlapping features such as myositis
    • Gastroesophageal reflux disease (GERD)
  • Less common symptoms include aseptic meningitis, hepatomegaly, and splenomegaly.
• Diagnosis
  • Involves clinical examination, patient history, and serological tests
  • Patients are positive for ANAs and anti-U1 RNP (see “Antibody diagnosis of autoimmune diseases.”).
    • ANA patterns help determine the type of immune disease.
    • Generally, all ANAs have a speckled pattern on immunofluorescence.
    • In addition to speckled, immunofluorescence patterns of ANA tests can also be:
      • Diffuse and peripheral in SLE
      • Nucleolar in SSc
• Treatment
  • 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

References:^[18]

The differential diagnoses listed here are not exhaustive.

General principles ^[8][14][19]

• 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. ^[8]

Cutaneous disease ^[8][19]

• Raynaud phenomenon (RP)
  • First line: calcium channel blockers, e.g., nifedipine (off-label)
  • Severe or refractory RP: add oral PDE–5 inhibitors (e.g., sildenafil) or IV iloprost
• Digital ulceration (DU)
  • First line: PDE-5 inhibitors (e.g., tadalafil) or IV iloprost
  • Severe or refractory DU: Consider bosentan.
• Cutaneous fibrosis
  • Early diffuse SSc; : phototherapy, and/or pharmacotherapy (e.g., methotrexate, or mycophenolate mofetil)
  • Severe or refractory fibrosis: cyclophosphamide or autologous HSCT
• Calcinosis cutis: carbon dioxide laser, or surgical removal of symptomatic lesions

Supportive care ^[6][20]

• 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. ^[14]
• Consider vasodilatory physical therapy and lymph drainage.
• Offer antihistamines for treatment of pruritus.
• Avoid beta blockers.

Avoid beta blockers, which can cause vasospasm and may worsen Raynaud phenomenon and digital ischemia in patients with SSc. ^[14]

Renal disease

• Scleroderma renal crisis
  • ACE inhibitors (ACEIs) are the mainstay of therapy
  • Captopril is most commonly used
  • See “Management of SRC.”
• Chronic kidney disease: See “Management of CKD.”

Cardiopulmonary disease

Manage specific cardiac and/or pulmonary conditions depending on manifestations (see “Clinical features”).

• Heart disease: depending on specific manifestation
  • See “Treatment of heart failure.”
  • See “Treatment of pericardial effusion and cardiac tamponade.”
  • See “Management of acute heart failure.”
  • See “Treatment of atrial fibrillation.”
  • See “Restrictive cardiomyopathy.”
• Pulmonary disease
  • Pulmonary hypertension
    • E.g., combination of ambrisentan and tadalafil
    • See “Treatment of pulmonary hypertension” and “Acute decompensation of PAH.”
  • Interstitial lung disease: systemic immunomodulatory medications, e.g., mycophenolate mofetil (See “Management of ILD.”)

Screen all patients for signs of respiratory distress as this can signify cardiopulmonary disease.

Systemic sclerosis is a cause of group 1 pulmonary hypertension, so affected individuals are likely to benefit from pulmonary vasodilators. ^[19]

Gastrointestinal disease ^[6][8][19]

• GERD: proton pump inhibitors (PPIs)
• GI motility disorder: prokinetic therapy, e.g., metoclopramide (off-label)
• SIBO: antibiotic therapy, e.g., rifaximin (off-label)

Scleroderma renal crisis (SRC) is a life-threatening complication of SSc characterized by the abrupt onset of hypertension and oliguric AKI. ^[21][22]

Management of SRC ^[21]

• Clinical suspicion: There are no validated diagnostic criteria.
  • Elevated blood pressure or an acute increase from baseline (e.g., SBP ↑ ≥ 30 mm Hg or DBP ↑ ≥ 20 mm Hg)
  • Other clinical features of SRC (e.g., oliguric AKI, MAHA)
• Blood pressure management ^[23]
  • First-line: Start or increase the dose of an ACEI (e.g., captopril).
    • Titrate to achieve a 10% reduction in blood pressure per day until normotensive. ^[19][21]
    • Continue therapy indefinitely.
  • Add additional antihypertensives as needed. ^[24]
  • Avoid beta blockers.
• Disposition
  • Consult nephrology as > 50% of patients require renal replacement therapy. ^[25]
  • Consider ICU admission.

Consider ICU admission for patients with features of end-organ damage, e.g., hypertensive encephalopathy, pulmonary edema, tachyarrhythmia, MAHA, or severe AKI requiring hemodialysis.

Normotensive blood pressure does not rule out SRC.

Secondary prevention ^[21]

• Advise regular blood pressure monitoring (e.g., 3–4 mornings per week) for patients with risk factors for SRC:
  • Demographics: older age, male sex
  • Disease pattern: diffuse SSc
  • Laboratory findings: anti-RNA polymerase III, ANA speckled pattern
  • Medications: glucocorticoid use
  • Examination: tendon friction rub, pericardial effusion
• Maintain a low threshold for urine dipstick test for protein.

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). ^[8][19]