Systemic Sclerosis - Scleroderma

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 – centromere pattern is relatively specific for systemic sclerosis (seen in ~95% of patients)
  • Antibody testing
    • Criteria antibodies
      • Scl-70 (anti-topoisomerase 1) is a specific marker of scleroderma when it is the only autoantibody present
        • 20-60% prevalence 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
        • Higher specificity than anti-RNA polymerase II
        • Predictive of rapid diffuse skin involvement and high risk for renal involvement
        • Most patients who are positive for this antibody are negative for anticentromere and anti-Scl-70
    • Other, less frequent antibodies include the following
      • Anti-fibrillarin/anti-U3-ribonucleoprotein (RNP)
        • Higher prevalence in individuals of African American descent, younger age of disease onset
        • May predict skeletal muscle involvement, pulmonary arterial hypertension, and renal disease
      • Anti-PM/Scl (PM/Scl-100)
        • Associated with polymyositis/scleroderma overlap disease
      • Anti-U1-RNP
        • Associated with SSc/SLE/polymyositis overlap syndromes when high titers observed
      • Anti-Th/To (7S/8S RNA)
        • May predict development of pulmonary hypertension
    • Negative antibody tests do 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

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/million
  • Age – peak onset 20-30 years
  • Sex – M<F, 1:3-8
  • Ethnicity – overall slight increase in frequency for African Americans compared to Caucasians
    • Marked increase in Choctaw Indians

Classification

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

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

    • Systemic sclerosis
      • Limited cutaneous disease – CREST syndrome variant (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia)
      • Diffuse cutaneous disease
      • Sine scleroderma (internal organ involvement only)
      • 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
    • Environmentally-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

  • Three 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 frequently identified antibodies
      • Anti-Th/To, anti-PM/Scl
      • Anti-U1-ribonucleoprotein (RNP)
      • Anti-fibrillarin/anti-U3-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 – pansclerotic in childhood, subcutaneous, profunda, eosinophilic
  • 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
    • CREST syndrome – calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia
    • 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 Antibody (ANA), IgG by IFA with Reflex by IFA Pattern 2008467
Method: Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Multiplex Bead Assay/Semi-Quantitative Immunoblot

Initial screen for connective tissue diseases

Test begins with IFA IgG; one or more reflexive tests may be added depending on results

  • Double-stranded DNA (dsDNA) antibody, IgG, by ELISA
  • Double-stranded DNA (dsDNA) antibody, IgG, by IFA (using Crithidiae luciliae)
  • Chromatin antibody, IgG
  • Extractable nuclear antigen antibodies (RNP, Smith, scleroderma, SSA, & SSB)
  • PM/Scl-100 antibody, IgG, by immunoblot
  • RNA polymerase III antibody, IgG

Only cytoplasmic, nuclear mitotic apparatus (NuMA), and/or nuclear dot pattern will be reported if observed; titers are not performed

Dual or mixed patterns will not be reflexed; additional testing for dual or mixed patterns should be determined by the ordering physician

A negative ANA by IFA test does not rule out the presence of connective tissue disease

 
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

Initial screen for connective tissue diseases

Detects antibodies against dsDNA, histone, SS-A (Ro), SS-B (La), Smith, snRNP/Sm, Scl-70, Jo-1, centromere, and an extract of lysed HEp-2 cells

Reflex pattern – if ANA detected by ELISA, then ANA by IFA titer added

   
Systemic Sclerosis Panel 2012057
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay/ Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Use to evaluate systemic sclerosis

Components include anti-nuclear antibody (ANA); scleroderma (Scl-70); and RNA polymerase III

Clinical sensitivity – ~≥90% for ANA by IFA test; ~80-85% for any of the titers for centromere, Scl-70, and RNA polymerase antibodies

Negative antibody test result does not exclude systemic sclerosis

 
Fibrillarin (U3 RNP) Antibody, IgG 2012173
Method: Semi-Quantitative Immunoblot

May predict skeletal muscle involvement and pulmonary arterial hypertension

Negative test result does not rule out the diagnosis of systemic sclerosis

Test results alone are not diagnostic; results should be used in conjunction with other laboratory tests and clinical findings

 
Myositis-Specific Antibody Panel 2010862
Method: Qualitative Immunoprecipitation/Semi-Quantitative Multiplex Bead Assay

Differential evaluation of patients with PM/DM and/or other connective tissue diseases or overlapping syndromes

Components include Jo-1, Mi-2, PL-7, PL-12, P155/140, EJ, SRP, and OJ

Results by themselves are not diagnostic; strong clinical correlation is recommended

 
Myositis Antibody Comprehensive Panel 2010851
Method: Qualitative Immunoprecipitation/Semi-Quantitative Multiplex Bead Assay

Differential evaluation of patients with PM/DM and/or other connective tissue diseases or overlapping syndromes

Components include SSA 52 and 60 (Ro); RNP (U1); Jo-1; Mi-2; PL-7; PL-12; P155/140 (TIF1-gamma); EJ; Ku; U2 sn; SRP; OJ; and PM/Scl complex antibodies

Results by themselves are not diagnostic; strong clinical correlation is recommended

 
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

   
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

Reflex pattern – if PM/Scl-100 ≥11 units, then ANA by IFA, IgG 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

   
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

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

Assess risk for renal crisis, diffuse cutaneous systemic sclerosis

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 

Reflex pattern – 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 52, SSA 60, and SSB Antibodies, IgG 0050317
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

Aids in initial diagnosis of connective tissue disease

Reflex pattern – if ANA IgG is detected by ELISA, then ANA IgG by IFA (using HEp-2 substrate) will be added; if ANA, IgG by IFA is confirmed positive with a titer of 1:40 or greater, then a titer and pattern will be reported; in addition, samples positive for ANA, IgG by IFA will reflex to double-stranded DNA (dsDNA) antibody, IgG by ELISA, RNP (U1) (Ribonucleic Protein) (ENA) antibody, IgG, Smith (ENA) antibody, IgG, SSA 52 and 60 (Ro) (ENA) antibodies, IgG, and SSB (La) (ENA) antibody, IgG. If double-stranded DNA (dsDNA) antibody, IgG by ELISA is detected, then double-stranded DNA (dsDNA) antibody, IgG by IFA (using Crithidia luciliae) will be added

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 52, SSA 60, and SSB) 0050652
Method: Semi-Quantitative Multiplex Bead Assay
SSA 52 and 60 (Ro) (ENA) Antibodies, IgG 2012074
Method: Semi-Quantitative Multiplex Bead Assay

Order as secondary screen based on results of ANA test or if ANA IFA is negative and there is strong suspicion for Sjögren syndrome, SLE, or myositis

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