Scleroderma - Systemic Sclerosis

Diagnosis

Indications for Testing

• Clinical presentation is characteristic for disease and should prompt lab confirmation

Laboratory Testing

• Initial testing – anti-nuclear antibodies (ANA) for both morphea and system sclerosis; CBC for morphea
  • ANA – nucleolar pattern is relatively specific for systemic sclerosis (seen in ~95% of patients)
• Antibody testing
  • Scl-70 (DNA anti-topoisomerase 1) is a specific marker of scleroderma when it is the only autoantibody present
    • Prevalence ranges from 20-60% in adult scleroderma
    • Low frequency in pediatric populations
    • Correlates with higher risk of interstitial lung disease (pulmonary fibrosis)
  • Anticentromere antibody (ACA)
    • Associated with limited systemic sclerosis
    • Prevalence of 60-80% in limited scleroderma, including CREST
    • High incidence of pulmonary hypertension
  • Other, less frequent antibodies include the following
    • Anti-fibrillarin/anti-U3-RNP
      • May predict skeletal muscle involvement and pulmonary arterial hypertension
      • Some studies suggest higher prevalence in individuals of African American descent
    • Anti-PM/SCL
      • Polymyositis and scleroderma overlap disease
    • Anti-RNA polymerase I/III
      • Invariably coexists with higher specificity than anti-RNA polymerase II
      • Predictive of rapid diffuse skin involvement and high risk for renal involvement
      • Most patients who are positive are negative for anticentromere and anti-Scl-70
    • Anti-U1-RNP
      • High titers are associated with SSc/SLE/polymyositis overlap syndromes
    • Anti-Th/To (7S/8S RNA)
      • May predict development of pulmonary hypertension
  • Negative antibody test result does not exclude systemic sclerosis

Histology

• Anti-fibrillarin/anti-U3-RNP – associated with internal organ involvement
• Anti-Th/To – associated with pulmonary fibrosis
• Morphea – early lesions characterized by dense infiltrate of lymphocytes, macrophages, plasma cells and occasionally eosinophils
• Systemic sclerosis – biopsy rarely required for diagnosis

Prognosis

• Markers not useful in prognostication

Differential Diagnosis

• Thyroid disorders
• Amyloidosis
• POEMS syndrome (Crow-Fukase syndrome)
• Diabetes mellitus
• Porphyria cutanea tarda
• Nephrogenic fibrosing dermopathy
• Scleromyxedema
• Scleredema
• Neoplasm (carcinoid in particular)
• Raynaud phenomenon
• Other connective tissue diseases
  • Mixed connective tissue disease
  • Inflammatory myopathies

Clinical Background

Systemic sclerosis is a chronic, multisystem autoimmune disorder characterized by thickening of the skin and accumulation of connective tissue in various organs.

Epidemiology

• Incidence – 3-20/1,000,000
• Age – peak onset 20s-30s
• Sex – M<F, 1:3-8
• Ethnicity – overall slight increase in frequency for African Americans compared to Caucasians
  • 10-fold increase in Choctaw Indians (southern Oklahoma)

Classification

• Classification of scleroderma (systemic sclerosis) and scleroderma-like disorders

  Classification of Scleroderma (Systemic Sclerosis) and Scleroderma-like Disorders

  Systemic sclerosis Limited cutaneous disease – CREST syndrome variant Diffuse cutaneous disease Sine scleroderma Undifferentiated connective tissue disease – multiple serologic and clinical features that do not meet American College of Rheumatology (ACR) criteria for rheumatic disease Overlap syndromes – systemic sclerosis plus polymyositis, rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) Localized scleroderma Plague morphea Generalized morphea Bullous morphea Deep morphea Linear scleroderma Chemical-induced scleroderma-like disorders Toxic-oil syndrome (rapeseed oil) Vinyl chloride-induced disease Bleomycin-induced fibrosis Pentazocine-induced fibrosis Epoxy- and aromatic hydrocarbons-induced fibrosis Eosinophilia-myalgia syndrome Nephrogenic system fibrosis (gadolinium-based contrast agents) Other scleroderma-like disorders Scleredema adultorum of Buschke Scleromyxedema (papular mucinosis) Chronic graft-vs-host disease Eosinophilic fasciitis Digital sclerosis in diabetes Primary amyloidosis and amyloidosis associated with multiple myeloma Paraneoplastic syndromes

Pathophysiology

• Pathologic remodeling of connective tissues is typified by 3 cardinal features
  • Fibrosis due to excessive collagen production
  • Vascular damage
  • Inflammation or autoimmune processes
• Pathologic antibodies
  • Commonly identified antibodies
    • Anti-centromere (ACA)
    • Anti-topoisomerase (Scl-70)
  • Less frequent antibodies
    • Anti-RNA polymerase I/III
    • Anti-Th/To, anti-PM/SCL
    • Anti-U1-ribonucleoprotein (RNP)
    • Anti-fibrillarin/anti-U3-ribonucleoprotein (RNP)

Clinical Presentation

• Morphea
  • Skin manifestations of systemic sclerosis without sclerodactyly or organ involvement
  • Morphea classifications
    • Plaque – guttate, generalized, nodular, lichen sclerosis, atrophoderma
    • Bullous
    • Linear
    • Deep – subcutaneous, profunda, eosinophilic, pansclerotic of children
• Systemic sclerosis
  • Dermatologic – thickening of skin, telangiectasis, hair loss, calcium deposits, Raynaud phenomenon, digital ulcers, sclerodactyly
  • Gastrointestinal – esophageal dysmotility, reflux, gastroparesis, malabsorption, constipation  
  • Pulmonary – interstitial fibrosis, pulmonary hypertension
  • Musculoskeletal – arthralgia, myalgia, arthritis, myopathy, weakness (usually proximal muscles)
  • Cardiovascular – myocardial fibrosis, pericarditis, valvular abnormalities, conduction problems (arrhythmias)
  • Renal – glomerulonephritis, scleroderma renal crisis
  • Head and neck – Sicca syndrome, hypothyroidism, Sjögren syndrome, blepharitis
  • Central nervous system – cranial and peripheral neuropathies, carpal tunnel syndrome
  • Genitourinary – erectile dysfunction, sexual dysfunction
  • Pediatric population
    • CREST unusual
    • Arthritis seen more often
    • Diffuse variant occurs most often (79%)

Treatment

• Remittive agents – cyclophosphamide
  • May alter the course of the disease; however, no definitive studies exist

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Smith (ENA) Antibody, IgG 0050085 Method: Semi-Quantitative Multiplex Bead Assay
Double-Stranded DNA (dsDNA) Antibody, IgG by ELISA with Reflex to dsDNA Antibody, IgG by IFA 0050215 Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody	dsDNA antibodies are screened using an ELISA assay  If dsDNA antibodies are detected, then dsDNA Antibody IgG by IFA (using Crithidia luciliae) will be performed
Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflexes to ANA, IgG by IFA and to dsDNA, RNP, Smith, SSA, and SSB Antibodies, IgG 0050317 Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay	If ELISA screen is positive, then IFA using HEp-2 substrate will be added; if confirmed by IFA, titer and pattern will be reported and testing for dsDNA antibody and ENA antibodies will be added
RNP (U1) (Ribonucleic Protein) (ENA) Antibody, IgG 0050470 Method: Semi-Quantitative Multiplex Bead Assay	Order as secondary screen based on results of ANA testing
Scleroderma (Scl-70) (ENA) Antibody, IgG 0050599 Method: Semi-Quantitative Multiplex Bead Assay	Order as secondary screen based on results of ANA testing
Extractable Nuclear Antigen Antibodies (RNP, Smith, SSA, & SSB) 0050652 Method: Semi-Quantitative Multiplex Bead Assay
Extractable Nuclear Antigen Antibodies (RNP, Smith, Scleroderma, SSA, & SSB) 0050653 Method: Semi-Quantitative Multiplex Bead Assay
SSA (Ro) (ENA) Antibody, IgG 0050691 Method: Semi-Quantitative Multiplex Bead Assay
SSB (La) (ENA) Antibody, IgG 0050692 Method: Semi-Quantitative Multiplex Bead Assay
Centromere Antibody, IgG 0050714 Method: Semi-Quantitative Multiplex Bead Assay	Order as secondary screen based on results of ANA testing
Histone Antibody, IgG 0050860 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Ribosomal P Protein Antibody 0099249 Method: Semi-Quantitative Multiplex Bead Assay
ssDNA Antibody, IgG 0099528 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Jo-1 Antibody, IgG 0099592 Method: Semi-Quantitative Multiplex Bead Assay

Diagnostic Algorithm

  Connective Tissue Disease Testing Algorithm