Mixed Connective Tissue Disease - MCTD

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

Indications for Testing

  • Rheumatologic disease presentation with overlap features

Criteria for Diagnosis

  • Alarcon-Segovia criteria (easiest to use)
    • Serological – antiribonucleoprotein (anti-RNP) ≥1:1,600 plus 3 or more of the following
      • Edema of hands
      • Synovitis
      • Myositis
      • Raynaud syndrome
      • Acrosclerosis

Laboratory Testing

  • Initial testing
    • CBC – mild anemia, leukopenia, thrombocytopenia common
    • C-reactive protein (CRP)
  • Connective tissue antibody testing
    • Initial screen – antinuclear antibodies (ANA)
      • Centromere pattern – diagnostic; usually >1:1,000
      • Speckled pattern – order extractable nuclear antigen (ENA)
    • Multiple autoantibodies may indicate MCTD or other autoimmune diseases
      • RNP antibodies found in 95-100% MCTD patients
      • RNP antibodies considered specific for syndrome if other antibodies negative
      • Other antibodies present include double-stranded DNA (dsDNA) (20-25%), Smith, and ribosomal-P
  • Other tests
    • Immunoglobulins – hypergammaglobulinemia
    • Rheumatoid factor, anti-citrullinated antibodies – often positive

Differential Diagnosis

  • Pulmonary function – test diffusing capacity of the lung for carbon monoxide (DLCO)

Mixed connective tissue disease (MCTD) is a systemic, autoimmune connective tissue disease. Clinically, patients exhibit varied combinations of features common to other autoimmune diseases such as systemic lupus erythematosus (SLE), polymyositis, rheumatoid arthritis, or systemic sclerosis (scleroderma). MCTD is often referred to as an overlap syndrome.

Epidemiology

  • Incidence – approximately 1/10,000
  • Age – mean onset is 10-29 years
  • Sex – M<F, 1:9

Pathophysiology

  • Most of the symptoms are a result of antibodies to uroporphyrin isomerase ribonucleoprotein (UI-RNP)
  • Antibodies bind to endothelial cells
  • Binding is pathogenic for blood vessels and causes damage
  • UI-RNP antibodies are not usually found in SLE and systemic sclerosis

Clinical Presentation

  • Constitutional – fatigue, fever, malaise
  • Vascular – Raynaud phenomenon
  • Musculoskeletal – arthritis, polymyositis, extremity edema (hands and fingers predominate), arthralgia, atherosclerosis, sclerodactyly
  • Neurologic – trigeminal neuralgia, aseptic meningitis
  • Pulmonary – pleuritis, fibrosis, pulmonary hypertension, shortness of breath, cough
  • Renal – glomerulonephritis; however, most patients lack renal disease
  • Gastrointestinal – esophageal dysmotility, gastroesophageal reflux disease, dyspepsia
  • Cardiac – pericarditis, chest pain
  • Dermatologic – alopecia, heliotrope rash, Gottron papules

Clinical Background

Epidemiology

  • Prevalence – rare, 0.3% of  pediatric rheumatology patients
  • Age – median is 11 years (range 2-16 years)
  • Sex – M:F; 1<6

Clinical Presentation

  • Constitutional – fatigue, fever
  • Dermatologic – Raynaud phenomenon (frequently first symptom), heliotrope rash, Gottron papules
  • Musculoskeletal – arthralgia, swollen hands and fingers, arthritis, myalgia
  • Ophthalmic – xerophthalmia, keratoconjunctivitis, sicca
  • Cardiac – pericarditis
  • Pulmonary – cough, shortness of breath, pleuritis
  • Gastrointestinal – dyspepsia, gastroesophageal reflux disease

Diagnosis

  • Refer to Diagnosis tab
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 

Low titer ANAs common with advancing age; certain drugs may also cause low titer ANAs

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

Rheumatoid Arthritis Panel with Reflex to Rheumatoid Factors, IgA, IgG, and IgM by ELISA 2003278
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Immunoturbidimetry/Quantitative Enzyme-Linked Immunosorbent 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]

General References

Aringer M, Smolen JS. Mixed connective tissue disease: what is behind the curtain? Best Pract Res Clin Rheumatol. 2007; 21(6): 1037-49. PubMed

Breda L, Nozzi M, De Sanctis S, Chiarelli F. Laboratory tests in the diagnosis and follow-up of pediatric rheumatic diseases: an update. Semin Arthritis Rheum. 2010; 40(1): 53-72. PubMed

Swanton J, Isenberg D. Mixed connective tissue disease: still crazy after all these years. Rheum Dis Clin North Am. 2005; 31(3): 421-36, v. PubMed

Swart JF, Wulffraat NM. Diagnostic workup for mixed connective tissue disease in childhood. Isr Med Assoc J. 2008; 10(8-9): 650-2. PubMed

References from the 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): 166-72. PubMed

Patil DT, Bennett AE, Mahajan D, Bronner MP. Distinguishing Barrett gastric foveolar dysplasia from reactive cardiac mucosa in gastroesophageal reflux disease. Hum Pathol. 2013; 44(6): 1146-53. PubMed

Medical Reviewers

Last Update: August 2016