Scleroderma - Systemic Sclerosis

Diagnosis

Indications for Testing

  • Skin thickening extending to metacarpophalangeal joint
  • Abnormal nailfold capillaries
  • Digital ulcers

Laboratory Testing

  • Initial testing – anti-nuclear antibodies (ANA) for both morphea and systemic sclerosis; CBC for morphea
    • ANA – nucleolar pattern is relatively specific for systemic sclerosis (seen in ~95% of patients)
  • Antibody testing – first three antibodies are considered criteria antibodies
    • Scl-70 (DNA anti-topoisomerase 1) is a specific marker of scleroderma when it is the only autoantibody present
      • Prevalence from 20-60% in adult scleroderma
      • Low frequency in pediatric populations
      • Correlates with higher risk of interstitial lung disease (pulmonary fibrosis)
    • Anticentromere antibody (ACA)
    • 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
    • Other, less frequent antibodies include the following
      • Anti-fibrillarin/anti-U3-RNP
        • Some studies suggest higher prevalence in individuals of African American descent
        • May predict skeletal muscle involvement and pulmonary arterial hypertension
      • Anti-PM/SCL (PM/Scl-100)
        • Associated with polymyositis/scleroderma overlap disease
      • 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

  • 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

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 (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia) 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)
      • Anti-RNA polymerase I/III
    • Less frequent antibodies
      • 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%)

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
Test Name and Number Recommended Use Limitations Follow Up
Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflex to ANA, IgG by IFA 0050080
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

First-line test for connective tissue disease screening

If ANA antibodies are detected, IFA titer is added

   
Connective Tissue Diseases Profile 0051668
Method: Semi-Quantitative Multiplex Bead Assay

Aid in identifying specific connective tissue disease

Panel consists of Smith (ENA), RNP, SSA, SSB, Jo-1, RPP, Centromere and Scl-70 antibodies

   
RNA Polymerase III Antibody, IgG 2001601
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Assess risk for renal crisis, diffuse cutaneous systemic sclerosis

   
PM/Scl-100 Antibody, IgG, by Immunoblot with Reflex to ANA IFA 2003040
Method: Semi-Quantitative Immunoblot/Semi-Quantitative Indirect Fluorescent Antibody

Aid in identifying specific form of scleroderma

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Assess for presence of eosinophilia if morphea present

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