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

• Other connective tissue diseases
  • SLE
  • Inflammatory myopathies
  • Sjögren syndrome
  • Systemic sclerosis – scleroderma
  • Undifferentiated connective tissue disease
• Rheumatoid arthritis
• Vasculitis
• Paraneoplastic neurological syndrome
• Endocarditis
• Fibromyalgia
• Chronic fatigue syndrome
• Sarcoidosis
• Nephrotic syndrome
• Acute poststreptococcal glomerulonephritis

Monitoring

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
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

Diagnostic Algorithm

  Connective Tissue Disease Testing Algorithm