Mixed Connective Tissue Disease - MCTD

Diagnosis

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
    • ESR – extremely elevated levels suggest possible infectious process
  • 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 positive antibodies include double-stranded DNA (dsDNA) (20-25%), Smith and ribosomal-P
  • Other tests
    • Immunoglobulins – hypergammaglobulinemia
    • Rheumatoid factor – often positive

Differential Diagnosis

Monitoring

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

Clinical Background

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

  • 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
  • Gastrointestinal – esophageal dysmotility, gastroesophageal reflux disease, dyspepsia
  • Cardiac – pericarditis, chest pain
  • Dermatologic – alopecia, heliotrope rash, Gottron papules

Pediatrics

Clinical Background

Epidemiology

  • Prevalence – 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

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
Test Name and Number Recommended Use Limitations Follow Up
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Detect anemia, leukopenia, thrombocytopenia

   
Sedimentation Rate, Westergren (ESR) 0040325
Method: Visual Identification

Detect infectious process

   
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

First-line test for connective tissue disease screening

All ELISA results reported as Detected are further tested by IFA

ANA ELISA screen is designed to detect antibodies against dsDNA, histone, SS-A (Ro), SS-B (La), Smith, snRNP/Sm, Scl-70, Jo-1, centromere, and an extract of lysed HEp-2 cells

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

Clarify pattern result from ANA

Panel includes Smith (ENA), RNP, SSA, SSB, Jo-1, RPP, centromere and Scl-70 antibodies

   
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

Diagnose and prognosticate rheumatoid arthritis

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Immunoglobulins, CSF Quantitative 0050631
Method: Quantitative Nephelometry

Detect hypergammaglobulinemia

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

dsDNA antibodies are screened using ELISA assay 

If dsDNA antibodies are detected, then dsDNA Antibody IgG by IFA (using Crithidia luciliae) is performed

Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflexes to ANA, IgG by IFA and to dsDNA, RNP, Smith, SSA, and SSB Antibodies, IgG 0050317
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

If ELISA screen is positive, then IFA using HEp-2 substrate will be added; if confirmed by IFA, titer and pattern will be reported and testing for dsDNA antibody and ENA antibodies will be added

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

Order as secondary screen based on results of ANA test

Scleroderma (Scl-70) (ENA) Antibody, IgG 0050599
Method: Semi-Quantitative Multiplex Bead Assay
Extractable Nuclear Antigen Antibodies (RNP, Smith, SSA, & SSB) 0050652
Method: Semi-Quantitative Multiplex Bead Assay

4 panel test

Extractable Nuclear Antigen Antibodies (RNP, Smith, Scleroderma, SSA, & SSB) 0050653
Method: Semi-Quantitative Multiplex Bead Assay

Clarify pattern result from ANA; may help differentiate among MCTD, rheumatoid arthritis, scleroderma, Sjögren syndrome and SLE

SSA (Ro) (ENA) Antibody, IgG 0050691
Method: Semi-Quantitative Multiplex Bead Assay

Order as secondary screen based on results of ANA test

SSB (La) (ENA) Antibody, IgG 0050692
Method: Semi-Quantitative Multiplex Bead Assay

Order as secondary screen based on results of ANA test

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