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

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

Tests generally appear in the order most useful for common clinical situations

Guidelines

• Avouac J, Fransen J, Walker UA, Riccieri V, Smith V, Muller C, Miniati I, Tarner IH, Randone SB, Cutolo M, Allanore Y, Distler O, Valentini G, Czirjak L, Muller-Ladner U, Furst DE, Tyndall A, Matucci-Cerinic M. Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group. Ann Rheum Dis. 2011; 70 (3) :476-481.PubMed
• Kowal-Bielecka O, Landewe R, Avouac J, Chwiesko S, Miniati I, Czirjak L, Clements P, Denton C, Farge D, Fligelstone K, Foldvari I, Furst DE, Muller-Ladner U, Seibold J, Silver RM, Takehara K, Toth BG, Tyndall A, Valentini G, van den Hoogen F, Wigley F, Zulian F, Matucci-Cerinic M. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis. 2009; 68 (5) :620-628.PubMed
• Zulian F, Woo P, Athreya BH, Laxer RM, Medsger TA Jr, Lehman TJ, Cerinic MM, Martini G, Ravelli A, Russo R, Cuttica R, de Oliveira SK, Denton CP, Cozzi F, Foeldvari I, Ruperto N. The Pediatric Rheumatology European Society/American College of Rheumatology/European League against Rheumatism provisional classification criteria for juvenile systemic sclerosis. Arthritis Rheum. 2007; 57 (2) :203-212.PubMed

General

• Basu D, Reveille JD. Anti-scl-70. Autoimmunity. 2005; 38 (1) :65-72.PubMed
• Castro SV, Jimenez SA. Biomarkers in systemic sclerosis. Biomark Med. 2010; 4 (1) :133-147.PubMed
• Chung L, Lin J, Furst DE, Fiorentino D. Systemic and localized scleroderma. Clin Dermatol. 2006; 24 (5) :374-392.PubMed
• Foeldvari I. Current developments in pediatric systemic sclerosis. Curr Rheumatol Rep. 2009; 11 (2) :97-102.PubMed
• Gilliland BC. Systemic Sclerosis (Scleroderma) and Related Disorders. In Kasper D et al. eds. Harrison's Principles of Internal Medicine, 17th ed. New York: McGraw-Hill, 2008. pp. 2096-2106.
• Hachulla E, Launay D. Diagnosis and classification of systemic sclerosis. Clin Rev Allergy Immunol. 2011; 40 (2) :78-83.PubMed
• Scleroderma Foundation. Scleroderma Foundation. Danvers: MA [Last Updated: 9 Apr 2009; Accessed: 30 May 2008] 
• Steen VD. The many faces of scleroderma. Rheum Dis Clin North Am. 2008; 34 (1) :1-15.PubMed
• Walker JG, Fritzler MJ. Update on autoantibodies in systemic sclerosis. Curr Opin Rheumatol. 2007; 19 (6) :580-591.PubMed
• Wooten M. Systemic sclerosis and malignancy: a review of the literature. South Med J. 2008; 101 (1) :59-62.PubMed

ARUP Institute for Clinical and Experimental Pathology®

• Jaskowski TD, Schroder C, Martins TB, Mouritsen L, Hill HR. Comparison of three commercially available enzyme immunoassays for the screening of autoantibodies to extractable nuclear antigens. J Clin Lab Anal. 1995; 9 (3) :166-172.PubMed

Connective Tissue Diseases
Cryoglobulinemia
Inflammatory Myopathies
Mixed Connective Tissue Disease
Sjögren Syndrome
Systemic Lupus Erythematosus
Vasculitis