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
    • 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

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

  • 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

Pediatrics

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

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
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

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

Reflex pattern – if ANA are detected by ELISA, then ANA by IFA titer will be added

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

Confirmatory tests for specific connective tissue disease

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

Reflex pattern – if CCP IgG ≥20 Units and/or rheumatoid factor ≥15 IU/mL, then rheumatoid factor, IgG/IgM/IgA by EIA will be performed

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Detect anemia, leukopenia, thrombocytopenia

C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Preferred test to detect inflammatory processes

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

Nonspecific test used to detect inflammation associated with infections

Immunoglobulins, CSF Quantitative 0050631
Method: Quantitative Nephelometry

Detect hypergammaglobulinemia

Smith (ENA) Antibody, IgG 0050085
Method: Semi-Quantitative Multiplex Bead Assay

Secondary screening for SLE based on ANA results

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

Secondary screening for SLE based on ANA results

Reflex pattern – If dsDNA IgG antibody is 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 52, SSA 60, and SSB Antibodies, IgG 0050317
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

Aids in initial diagnosis of connective tissue disease

Reflex pattern – if ANA IgG is detected by ELISA, then ANA IgG by IFA (using HEp-2 substrate) will be added; if ANA, IgG by IFA is confirmed positive with a titer of 1:40 or greater, then a titer and pattern will be reported; in addition, samples positive for ANA, IgG by IFA will reflex to double-stranded DNA (dsDNA) antibody, IgG by ELISA, RNP (U1) (Ribonucleic Protein) (ENA) antibody, IgG, Smith (ENA) antibody, IgG, SSA 52 and 60 (Ro) (ENA) antibodies, IgG, and SSB (La) (ENA) antibody, IgG. If double-stranded DNA (dsDNA) antibody, IgG by ELISA is detected, then double-stranded DNA (dsDNA) antibody, IgG by IFA (using Crithidia luciliae) will be added

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

May be useful in the evaluation of neuropsychiatric SLE, positive predictive value is variable

Scleroderma (Scl-70) (ENA) Antibody, IgG 0050599
Method: Semi-Quantitative Multiplex Bead Assay
Extractable Nuclear Antigen Antibodies (RNP, Smith, SSA 52, SSA 60, and SSB) 0050652
Method: Semi-Quantitative Multiplex Bead Assay

4 panel test

Systemic Sclerosis Panel 2012057
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay/ Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Use to evaluate systemic sclerosis

Components include anti-nuclear antibody (ANA); scleroderma (Scl-70); and RNA polymerase III

SSA 52 and 60 (Ro) (ENA) Antibodies, IgG 2012074
Method: Semi-Quantitative Multiplex Bead Assay

Order as secondary screen based on results of ANA test or if ANA IFA is negative and Sjögren syndrome, SLE, or myositis is strongly suspected.

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