Systemic Sclerosis - Scleroderma

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Content

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

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

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

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

Limitations

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

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

Limitations

Negative antibody test result does not exclude systemic sclerosis

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

Limitations

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

Limitations

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

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

Limitations

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

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

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

RNP (U1) (Ribonucleic Protein) (ENA) Antibody, IgG 0050470
Method: Semi-Quantitative Multiplex Bead Assay

Additional Tests Available

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Comments

Assess for presence of eosinophilia if morphea present

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

Comments

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

Comments

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

Comments

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

Comments

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

Comments

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

Comments

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

Guidelines

Avouac J, Fransen J, Walker U, Riccieri V, Smith V, Muller C, Miniati I, Tarner I, Randone B, Cutolo M, Allanore Y, Distler O, Valentini G, Czirjak L, Müller-Ladner U, Furst D, Tyndall A, Matucci-Cerinic M, EUSTAR Group. 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): 476-81. PubMed

van den Hoogen F, Khanna D, Fransen J, Johnson S, Baron M, Tyndall A, Matucci-Cerinic M, Naden R, Medsger T, Carreira P, Riemekasten G, Clements P, Denton C, Distler O, Allanore Y, Furst D, Gabrielli A, Mayes M, van Laar J, Seibold J, Czirjak L, Steen V, Inanc M, Kowal-Bielecka O, Müller-Ladner U, Valentini G, Veale D, Vonk M, Walker U, Chung L, Collier D, Csuka M, Fessler B, Guiducci S, Herrick A, Hsu V, Jimenez S, Kahaleh B, Merkel P, Sierakowski S, Silver R, Simms R, Varga J, Pope J. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013; 72(11): 1747-55. PubMed

van den Hoogen F, Khanna D, Fransen J, Johnson S, Baron M, Tyndall A, Matucci-Cerinic M, Naden R, Medsger T, Carreira P, Riemekasten G, Clements P, Denton C, Distler O, Allanore Y, Furst D, Gabrielli A, Mayes M, van Laar J, Seibold J, Czirjak L, Steen V, Inanc M, Kowal-Bielecka O, Müller-Ladner U, Valentini G, Veale D, Vonk M, Walker U, Chung L, Collier D, Csuka M, Fessler B, Guiducci S, Herrick A, Hsu V, Jimenez S, Kahaleh B, Merkel P, Sierakowski S, Silver R, Simms R, Varga J, Pope J. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 2013; 65(11): 2737-47. PubMed

General References

Castro S, Jimenez S. Biomarkers in systemic sclerosis. Biomark Med. 2010; 4(1): 133-47. PubMed

Chung L, Lin J, Furst D, Fiorentino D. Systemic and localized scleroderma. Clin Dermatol. 2006; 24(5): 374-92. PubMed

Czömpöly T, Simon D, Czirjak L, Németh P. Anti-topoisomerase I autoantibodies in systemic sclerosis. Autoimmun Rev. 2009; 8(8): 692-6. PubMed

Foeldvari I. Current developments in pediatric systemic sclerosis. Curr Rheumatol Rep. 2009; 11(2): 97-102. PubMed

Hachulla E, Launay D. Diagnosis and classification of systemic sclerosis. Clin Rev Allergy Immunol. 2011; 40(2): 78-83. PubMed

Mehra S, Walker J, Patterson K, Fritzler M. Autoantibodies in systemic sclerosis. Autoimmun Rev. 2013; 12(3): 340-54. PubMed

Scleroderma Foundation. Scleroderma Foundation. Danvers, MA [Accessed: Nov 2015]

Steen V. The many faces of scleroderma. Rheum Dis Clin North Am. 2008; 34(1): 1-15; v. PubMed

Torok K. Pediatric scleroderma: systemic or localized forms. Pediatr Clin North Am. 2012; 59(2): 381-405. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Copple S, Giles R, Jaskowski T, Gardiner A, Wilson A, Hill H. Screening for IgG antinuclear autoantibodies by HEp-2 indirect fluorescent antibody assays and the need for standardization. Am J Clin Pathol. 2012; 137(5): 825-30. PubMed

Jaskowski T, Schroder C, Martins T, Mouritsen L, Hill H. Comparison of three commercially available enzyme immunoassays for the screening of autoantibodies to extractable nuclear antigens. J Clin Lab Anal. 1995; 9(3): 166-72. PubMed

Medical Reviewers

Last Update: December 2015