Connective Tissue Diseases

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

Indications for Testing

  • Patient with systemic symptoms, including arthralgias, arthritis, skin rashes, anemia, renal dysfunction, pleuritis, pericarditis

Laboratory Testing

  • Nonspecific testing
    • CBC – rule out infection
    • C-reactive protein (CRP)
    • Antinuclear antibodies (ANA) testing
      •  ANA, IgA, by ELISA
        • Negative – possible scenarios
          • No connective tissue disease (CTD) present
          • False-negative result – consider systemic sclerosis (scleroderma SSc), polymyositis/dermatomyositis (PM/DM), inactive systemic lupus erythematosus (SLE)
            • If strong suspicion for CTD, consider disease-specific antibody tests or panels
            • Positive – ANA HEp-2, IgG, by IFA (result pattern suggests underlying disease)
              • ANA reported patterns and diagnoses
                • Centromere – limited cutaneous scleroderma (lcSSc), CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia)
                • Cytoplasmic – PM, DM, SLE, SSc
                • Peripheral/rim/homogenous – SLE, drug-induced lupus erythematosus (DIL)
                • Nucleolar – SLE, SSc, PM DM
                • Speckled – SLE, Sjögren syndrome, mixed connective tissue disease (MCTD)/undifferentiated connective tissue disease (UCTD), diffuse cutaneous scleroderma (dcSSc), unidentified specificities or markers of low prevalence in CTD – see Connective Tissue Disease Testing Algorithm for more specific antibody testing patterns
              • False-positive results may be induced by age, certain infections, cancers, and drugs
              • ANA may be positive in inflammatory diseases (eg, autoimmune liver diseases)
              • Titer level has no bearing on diagnosis or disease severity once it is above established normal level
      • Other testing
        • Rheumatoid factor IgM antibodies – if musculoskeletal complaints are present
        • If suspicion for connective tissue disease is low, consider drug-induced lupus erythematosus (DIL), chronic autoimmune disease, chronic hepatitis C virus
        • Urinalysis – rule out glomerulonephritis associated with connective tissue disease
        • Anti-neutrophil cytoplasmic antibodies (ANCA) – rule out vasculitis associated with connective tissue disease

    Differential Diagnosis

    • Once diagnosis has been made, use monitoring tests based on organ involvement
      • Urinalysis – acceptable screen for renal disease
      • If cytopenias present, follow with sequential CBCs
      • Certain treatment drugs require liver function testing

    Several autoimmune connective tissue diseases may present with similar features. These diseases include systemic lupus erythematosus, Sjögren syndrome, mixed connective tissue disease, systemic sclerosis (scleroderma), inflammatory myopathies (polymyositis/dermatomyositis [PM/DM]), and undifferentiated connective tissue disease.

    Epidemiology

    • Incidence – 15-50/100,000, depending on disease
    • Age – onset is 15-40 years; peak onset in 20s
    • Sex – M<F, 1:6-10

    Pathophysiology

    • Circulating antigen-antibody complexes affect a variety of organs
    • Multisystem disease presentation
    • Antigen/antibody complexes affect a variety of organs in connective tissue diseases
    • ANA antibodies are the most common antibodies and may precede the onset of connective tissue disease
    • Certain antibodies may show specificity for certain diseases (eg, SSA 52, SSA 60, and SSB antibodies for Sjögren syndrome)
    • ANA antibodies are not specific for connective tissue disease and may also be associated with
      • Infectious diseases
      • Cancers
      • Other autoimmune disorders (eg, autoimmune liver disease)
      • Advanced age

    Clinical Presentation

    • Cardiopulmonary – pleuritis, pericarditis, fibrosis, chest pain
    • Constitutional – fever, anorexia, weight loss
    • Dermatologic – skin rashes, Raynaud phenomenon, photosensitivity
    • Gastrointestinal – gastroesophageal reflux disease
    • Hematologic – cytopenias (involving neutrophils, erythrocytes, and platelets)
    • Musculoskeletal – arthralgias, arthritis, synovitis, myopathy
    • Neurologic – seizures, encephalopathy
    • Otorhinolaryngologic – sicca syndrome, oral ulcers
    • Renal – proteinuria, glomerulonephritis

    Clinical Background

    Epidemiology

    • Incidence – varies by disease but lower than in adults
    • Sex – M<F for most disorders
    • Age – presents more often >10 years

    Clinical Presentation

    • Cardiopulmonary – chest pain, pericarditis, pleuritis
    • Constitutional – fever, anorexia, weight loss (most common)
    • Dermatologic – skin rash, Raynaud syndrome, photosensitivity
    • Gastrointestinal – abdomen pain, diarrhea, hepatitis
    • Musculoskeletal – arthralgias, arthritis, synovitis, myopathy, weakness

    Diagnosis

    Indications for Testing

    • Appropriate clinical presentation, including arthritis, arthralgias, skin rashes, anemia, pleuritis, pericarditis

    Laboratory Testing

    • Nonspecific testing
      • Refer to Diagnosis tab
    • ANA testing
      • Refer to Diagnosis tab and Connective Tissue Disease Testing Algorithm
    • Other testing
      • Rheumatoid factor IgM antibodies – rule out juvenile idiopathic arthritis if musculoskeletal complaints are present

    Differential Diagnosis

    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/Qualitative 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

    Limitations 

    Results are not disease specific

    ANA ELISA assays have lower sensitivities for antibodies associated with nucleolar and specked ANA-IFA patterns

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

    Systemic Sclerosis Comprehensive Panel 2013325
    Method: Qualitative 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

    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

    Panel does not include Th/To

    Polymyositis and Dermatomyositis Panel 2013992
    Method: Qualitative Immunoprecipitation/Semi-Quantitative Multiplex Bead Assay/Qualitative Immunoblot

    Limitations 

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

    Negative results do not rule out a diagnosis of inflammatory myopathy or overlap syndrome

    Polymyositis Panel 2013990
    Method: Qualitative Immunoprecipitation/Semi-Quantitative Multiplex Bead Assay

    Dermatomyositis Panel 2013991
    Method: Qualitative Immunoprecipitation/Qualitative Immunoblot

    Interstitial Lung Disease Panel 2013993
    Method: Qualitative Immunoprecipitation/Semi-Quantitative Multiplex Bead Assay/Qualitative Immunoblot/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Immunoturbidimetry

    Myositis Extended Panel 2013961
    Method: Qualitative Immunoprecipitation/Semi-Quantitative Multiplex Bead Assay/Qualitative Immunoblot

    Limitations 

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

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

    Rheumatoid Arthritis Panel 2003277
    Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Immunoturbidimetry

    Fibrillarin (U3 RNP) Antibody, IgG 2012173
    Method: Qualitative 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

    Anti-Neutrophil Cytoplasmic Antibody with Reflex to Titer and MPO/PR-3 Antibodies 2002068
    Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

    Guidelines

    Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Jan 2017]

    Meroni PL, Schur PH. ANA screening: an old test with new recommendations. Ann Rheum Dis. 2010; 69(8): 1420-2. 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 ME, 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. Arthritis Rheum. 2013; 65(11): 2737-47. PubMed

    General References

    Fritzler MJ. The antinuclear antibody test: last or lasting gasp? Arthritis Rheum. 2011; 63(1): 19-22. PubMed

    Ghirardello A, Bendo R, Rampudda ME, Bassi N, Zampieri S, Doria A. Commercial blot assays in the diagnosis of systemic rheumatic diseases. Autoimmun Rev. 2009; 8(8): 645-9. PubMed

    Kumar S, Aggarwal A. Approach to a patient with connective tissue disease. Indian J Pediatr. 2010; 77(10): 1157-64. PubMed

    Liu C, Ahearn JM. The search for lupus biomarkers. Best Pract Res Clin Rheumatol. 2009; 23(4): 507-23. PubMed

    Mammen AL. Dermatomyositis and polymyositis: Clinical presentation, autoantibodies, and pathogenesis. Ann N Y Acad Sci. 2010; 1184: 134-53. PubMed

    Schulte-Pelkum J, Fritzler M, Mahler M. Latest update on the Ro/SS-A autoantibody system. Autoimmun Rev. 2009; 8(7): 632-7. PubMed

    Singh S, Mehra S. Approach to polyarthritis. Indian J Pediatr. 2010; 77(9): 1005-10. PubMed

    Vaz CC, Couto M, Medeiros D, Miranda L, Costa J, Nero P, Barros R, Santos MJ, Sousa E, Barcelos A, Inês L. Undifferentiated connective tissue disease: a seven-center cross-sectional study of 184 patients. Clin Rheumatol. 2009; 28(8): 915-21. PubMed

    Medical Reviewers

    Last Update: December 2016