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 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

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 

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

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

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 syndrome

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 

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

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

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

American Society for Clinical Pathology. Choosing Wisely - Five Things Physicians and Patients Should Question. An initiative of the ABIM Foundation. [Last revision Feb 2015; Accessed: Jan 2016]

Meroni PLuigi, 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 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. 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 MElisa, 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: August 2016