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

• 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

• 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

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

Tests generally appear in the order most useful for common clinical situations

General

• Aringer M, Smolen JS. Mixed connective tissue disease: what is behind the curtain?. Best Pract Res Clin Rheumatol. 2007; 21 (6) :1037-1049.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
• Gaubitz M. Epidemiology of connective tissue disorders. Rheumatology (Oxford). 2006; 45 Suppl 3 :iii3-iii4.PubMed
• Greidinger EL, Hoffman RW. Autoantibodies in the pathogenesis of mixed connective tissue disease. Rheum Dis Clin North Am. 2005; 31 (3) :437-50, vi.PubMed
• Lyons R, Narain S, Nichols C, Satoh M, Reeves WH. Effective use of autoantibody tests in the diagnosis of systemic autoimmune disease. Ann N Y Acad Sci. 2005; 1050 :217-228.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) :650-652.PubMed

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) :166-172.PubMed

Acute Phase Proteins
Connective Tissue Diseases
Cryoglobulinemia
Inflammatory Myopathies
Rheumatoid Arthritis
Scleroderma
Sjögren Syndrome
Systemic Lupus Erythematosus
Thiopurine Methyltransferase Activity
Vasculitis