Scleroderma Diagnosis

• Diagnosis is based on medical history, clinical presentation and diagnostic tests

2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Classification Criteria for Scleroderma/Systemic Sclerosis (SSc)

• A total score of ≥9 classifies a patient as having SSc
  • Presence of skin thickening of the fingers extending proximal to the metacarpophalangeal (MCP) joints = 9
  • Swollen digits = 2; symptoms of fingers distal to the MCP joints = 4 (use only the higher score)
  • Fingertip ulcers = 2; fingertip pitting scars = 3 (use only the higher score)
  • Abnormal nailfold capillaries = 2
  • Telangiectasia = 2
  • Interstitial lung disease (ILD) or pulmonary arterial hypertension (PAH) = 2
  • Raynaud’s phenomenon = 3
  • SSc-related autoantibodies (anticentromere antibody, anti-DNA topoisomerase I, anti-RNA polymerase III) = 3

Localized

• Usually affects only the skin but may spread to the joints, bones, muscles and nerve tissues
• Not associated with Raynaud’s phenomenon or significant internal organ manifestations
  
  • Morphea
    
    • Circumscribed (plaque) 
      • ≥1 discolored patches on the skin with sclerotic changes in 1 anatomic site  
      • Involvement confined in the subcutaneous tissue  
      • Very localized form of scleroderma
    • Linear
      • Streaks or band of thick hard skin on the arms and legs, and subcutaneous tissue abnormalities in dermatomal distribution affecting usually 1 side of the body
      • Most common form of morphea in children  
      • Associated with impairment of growth of affected extremity  
      • En coup de sabre is a type of linear morphea in which there are sclerotic lesions on the face, scalp or forehead  
    • Generalized
      • ≥4 plaques (similar to circumscribed morphea) involving at least 2 anatomic sites often on the limbs or trunk  
    • Bullous
      • May occur in other forms of morphea  
    • Deep
      • Most disabling form of morphea primarily involving the subcutaneous tissue
      • Most uncommon form of morphea in children

Systemic (SSc)

• Hardening of the skin and Raynaud’s phenomenon are the clinical hallmarks of the disease
• Usually occurs in women ages 30-50 years old
• Assessment should also include screening for autoimmune conditions associated with SSc and identifying visceral complications and assessing its severity
  
  • Limited cutaneous
    
    • Skin thickening is mainly limited in the forearms, hands, face and feet (acral distribution), has prominent vascular presentation and may also affect the lungs and digestive system [eg PAH, severe gastroesophageal reflux disease (GERD), ILD] 
    • Physical exam shows telangiectasia, calcinosis cutis, sclerodactyly and digital ischemic complications
  • Diffuse cutaneous
    
    • More extensive skin involvement affecting acral skin and trunk (extends above the elbows and/or knees) with more serious and extensive internal organ involvement (eg heart, lung, gastrointestinal and kidneys) 
    • Tendon friction rubs and pigment changes are the common physical exam findings
  • SSc sine scleroderma
    
    • Type of systemic scleroderma that only affects the internal organs with no skin involvement
    • Anti-Scl-70, ACA, or anti-RNA polymerase I, II, or III may be present
  • Overlap syndromes
    
    • Type of systemic scleroderma with concomitant autoimmune rheumatic disease (eg rheumatoid arthritis, SLE, polymyositis, dermatomyositis, vasculitis, Sjögren’s syndrome)
  • Pre-scleroderma
    
    • Raynaud’s phenomenon, nailfold capillary changes and antibodies such as anti-Scl-70 and RNA polymerase I, II, or III are present
  • Environmentally-induced scleroderma
    • Positive for history of exposure to a scleroderma-inducing environmental agent and diffuse skin sclerosis

Duration of Disease Progression 

• Reflects risk of visceral damage: Renal complications occur in recent diffuse cutaneous SSc with progression of <3-5 years while pulmonary fibrosis occurs with disease progression of <5 years
  • PAH and cardiac and gastrointestinal complications can arise later but may also occur early

• There is no definitive diagnostic test for scleroderma
• Serologic tests confirm but not exclude the diagnosis of scleroderma

Anticentromere Antibodies (ACA)

• Highly specific and moderately sensitive for limited cutaneous SSc 
• Associated with higher risk of esophageal disease, PAH or severe peripheral vascular disease

Antinuclear Antibodies (ANA) Panel

• Will show homogeneous, speckled or nucleolar staining patterns
• Nucleolar pattern is most specific for SSc

Anti-beta2-glycoprotein I (β2GPI) Antibodies

• Usually present in scleroderma patients with macrovascular disease
• Associated with higher risk of active digital ischemia, loss of digits secondary to ischemia and PAH

Anti-DNA Topoisomerase I (Anti-Scl-70)

• Highly specific and moderately sensitive for diffuse cutaneous SSc
• Associated with higher risk of severe ILD or lung fibrosis or severe peripheral vascular disease

Anti-PM-Scl Autoantibodies

• Clinically associated with limited cutaneous SSc overlap syndromes and usually present in systemic scleroderma patients with myositis

Anti-RNA Polymerase II

• Also present in patients with diffuse SSc and systemic lupus erythematosus (SLE)

Anti-RNA Polymerase III

• Highly specific and moderately sensitive for diffuse cutaneous SSc
• Associated with higher risk of scleroderma renal crisis, malignancy or skin involvement

U1-RNP Antibodies

• Clinically associated with limited cutaneous SSc with muscle involvement and arthritis

U3-RNP (Fibrillarin) Antibodies

• Clinically associated with diffuse cutaneous SSc and poor outcome
• Associated with higher risk of SSc-associated PAH, ILD, renal crisis, small intestinal damage and skeletal muscle involvement

Organ-specific Assessments

• Joint radiographs for arthritis, bone densitometry for possible osteoporosis
• Hemoglobin, levels of ferritin and vitamins A, D, E, K, B1, B9 and B12, prealbumin, barium swallow (cine esophagography), endoscopy, esophageal manometry and colonoscopy for gastrointestinal complications
• Chest radiograph, pulmonary function tests, high-resolution lung CT scan, bronchoscopy with biopsy, gallium lung scan, bronchoalveolar lavage to check for pulmonary complications
• Troponin, ECG ambulatory (Holter), ECG monitoring, Doppler echocardiography, cardiac MRI, cardiac catheterization to assess for cardiac complications
• Renal biopsy, creatinine, creatinine clearance, and urinalysis for renal complications
• Urine culture, 24-hour protein measurement, creatinine, plasma electrolytes, urea, haptoglobin, lactate dehydrogenase, reticulocytes, free bilirubin, schizocytes on a blood smear, renal ultrasound and Doppler ultrasound of the renal arteries for suspected scleroderma renal crisis
• Skin biopsy for localized scleroderma, periungual capillaroscopy for suspected SSc
• Creatine phosphokinase measurements, erythrocyte sedimentation rate and C-reactive protein measurements for myositis, malignancy or overlap of SSc with another autoimmune disease

PAH Screening in SSc   

• Early diagnosis and treatment of PAH may improve clinical outcomes in patients with SSc 
• The 6th World Symposium on Pulmonary Hypertension in 2018 recommends the use of transthoracic echocardiography (TTE) and the DETECT algorithm to annually screen for PAH in patients with SSc spectrum disorders and a diffusing capacity of the lung for carbon monoxide (DLCO) of <80% predicted  
  • DETECT algorithm uses the combination of pulmonary function testing (forced vital capacity/DLCO ratio) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels
  • Patients with positive screening tests are referred for right heart catheterization for confirmation of diagnosis
  • For patients with a DLCO of ≥80% predicted, consider an annual TTE 
• The Australian Scleroderma Interest Group (ASIG) algorithm requires fewer variables in the initial step with less restrictive inclusion criteria whereas DETECT is a more validated tool for patients meeting the inclusion criteria