Systemic Sclerosis - Scleroderma

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

Indications for Testing

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

Criteria for Diagnosis

Laboratory Testing

  • Initial testing – anti-nuclear antibodies (ANA) for both morphea and systemic sclerosis; CBC for morphea
    • ANA – (seen in ~95% of patients)
      • Centromere pattern is relatively specific for systemic sclerosis
      • ANA-antibody-negative systemic sclerosis (Salazar, 2015)  
        • Distinct subset of SSc with less vasculopathy, greater proportion of males, and possibly, more frequent lower GI involvement
  • Antibody testing
    • Criteria antibodies
      • Anti-Scl-70 (anti-topoisomerase 1) is a specific marker of scleroderma when it is the only autoantibody present
        • 20-60% prevalence in adult-onset scleroderma
        • Low frequency in pediatric populations
        • Correlates with higher risk of interstitial lung disease (pulmonary fibrosis)
      • Anticentromere antibody (ACA)
        • 60-80% prevalence in limited scleroderma, including CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia)
        • Associated with limited systemic sclerosis
        • High incidence of pulmonary hypertension
      • Anti-RNA polymerase 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 antibodies
    • 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, also called scleroderma, 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
    • Ten-fold 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
      • Anticentromere antibodies (ACA)
      • Anti-topoisomerase (Anti-Scl-70)
      • Anti-RNA polymerase III
    • Less frequently identified antibodies
      • Anti-Th/To, anti-PM/Scl
      • Anti-U3 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, telangiectasia, hair loss, calcium deposits, Raynaud phenomenon, digital ulcers, sclerodactyly
    • Gastrointestinal – esophageal dysmotility, gastroesophageal reflux disease, gastroparesis/constipation, malabsorption
    • Pulmonary – pulmonary hypertension leading to interstitial fibrosis
    • Musculoskeletal – arthralgias/myalgias, arthritis, myopathy (usually proximal)
    • Cardiovascular – myocardial fibrosis, pericarditis, valvular abnormalities, conduction abnormalities (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
    • Pediatric population
      • CREST syndrome – unusual
      • Arthritis – more common
      • Diffuse variant occurs most often (79%)​
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.

Systemic Scleroderma Comprehensive Panel 2013325
Method: Semi-Quantitative Immunoblot/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Limitations 

Negative antibody test result does not exclude SSc; 5-10% of SSc patients are ANA IFA negative

Panel does not include Th/To

Multiplex bead assay detects antibodies targeting the centromere protein B of the centromere complex

Centromere Antibody, IgG 0050714
Method: Semi-Quantitative Multiplex Bead Assay

Limitations 

Negative results do not rule out SSc

Follow-up 

If negative and suspicion for SSc exists, consider testing for other SSc antibodies

Scleroderma (Scl-70) (ENA) Antibody, IgG 0050599
Method: Semi-Quantitative Multiplex Bead Assay

Limitations 

Negative results do not rule out SSc

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

Limitations 

Negative results do not rule out SSc

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

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

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

Negative results do not rule out a diagnosis of IM or overlap syndromes

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

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 results do not rule out SSc

Panel does not include Th/To

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

Negative results do not rule out a diagnosis of IM or overlap syndromes

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

Guidelines

Avouac J, Fransen J, Walker UA, Riccieri V, Smith V, Muller C, Miniati I, Tarner IH, Randone B, Cutolo M, Allanore Y, Distler O, Valentini G, Czirjak L, Müller-Ladner U, Furst DE, 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

Pope JE, Johnson SR. New Classification Criteria for Systemic Sclerosis (Scleroderma) Rheum Dis Clin North Am. 2015; 41(3): 383-98. PubMed

van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, Allanore Y, Furst DE, Gabrielli A, Mayes MD, van Laar JM, Seibold JR, Czirjak L, Steen VD, Inanc M, Kowal-Bielecka O, Müller-Ladner U, Valentini G, Veale DJ, Vonk MC, Walker UA, Chung L, Collier DH, Csuka MEllen, Fessler BJ, Guiducci S, Herrick A, Hsu VM, Jimenez S, Kahaleh B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, Pope JE. 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

General References

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

Chung L, Lin J, Furst DE, 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 MJ. Autoantibodies in systemic sclerosis. Autoimmun Rev. 2013; 12(3): 340-54. PubMed

Salazar GA, Assassi S, Wigley F, Hummers L, Varga J, Hinchcliff M, Khanna D, Schiopu E, Phillips K, Furst DE, Steen V, Baron M, Hudson M, Taillefer SS, Pope J, Jones N, Docherty P, Khalidi NA, Robinson D, Simms RW, Silver RM, Frech TM, Fessler BJ, Molitor JA, Fritzler MJ, Segal BM, Al-Kassab F, Perry M, Yang J, Zamanian S, Reveille JD, Arnett FC, Pedroza C, Mayes MD. Antinuclear antibody-negative systemic sclerosis Semin Arthritis Rheum. 2015; 44(6): 680-6. PubMed

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

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

Torok KS. 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 SS, Giles R, Jaskowski TD, Gardiner AE, Wilson AM, Hill HR. 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 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): 166-72. PubMed

Medical Reviewers

Last Update: August 2016