eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Mixed Connective Tissue Disease

Author: Marisa S Klein-Gitelman, MD, MPH, Associate Professor of Pediatrics, Northwestern University Feinberg School of Medicine; Head, Division of Rheumatology, Children's Memorial Hospital
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Updated: Sep 29, 2009

Introduction

Background

In pediatrics, Kasukawa criteria are used most frequently in published series and have more conservative requirements. Mixed connective tissue disease remains a controversial diagnosis. Some rheumatologists view mixed connective tissue disease as a separate disease; others classify the disorder as an undifferentiated connective tissue disease or overlap syndrome, which may have features of lupus, progressive systemic sclerosis, rheumatoid arthritis, and myositis but should not have its own separate name.

Adding support to the concept of mixed connective tissue disease as a distinct entity, in 1993, Mairesse et al described an autoantibody to the constitutive 73-kD heat shock protein found at high levels exclusively in patients with mixed connective tissue disease.⁴ This autoantibody was found in reduced levels in patients with progressive systemic sclerosis and rheumatoid arthritis. The autoantibody was not found in significant quantities in patients with systemic lupus erythematosus (SLE) or myositis. This finding has not been duplicated and must be interpreted with caution. However, the authors redefine mixed connective tissue disease as "a core of minor symptoms (ie, Raynaud phenomenon, puffy fingers, mild myositis, and arthritis) associated significantly with anti-U1-68kD antibody, defining an undifferentiated connective tissue (UCTD) disease that may ultimately overlap with features of major connective tissue disease."

Although confusing, perhaps the best way to consider mixed connective tissue disease is as an undifferentiated connective tissue disease represented mostly by Raynaud phenomenon and anti-RNP antibody.

Pathophysiology

Mixed connective tissue disease has features of several autoimmune diseases. For more details see Juvenile Rheumatoid Arthritis, Neonatal Lupus and Cutaneous Lupus Erythematosus in Children, Systemic Lupus Erythematosus, Systemic Sclerosis, Sjogren Syndrome, Dermatomyositis, and Myositis Ossificans.

Frequency

United States

In a literature review, Michels counted 224 cases of mixed connective tissue disease.⁵ Pediatric-onset mixed connective tissue disease accounts for an estimated one quarter of all cases. Most large pediatric rheumatology centers in major cities have 5-15 active pediatric cases, although some studies estimate that mixed connective tissue disease occurs in 0.6% of all pediatric rheumatology patients.

International

US data are derived from international data.

Mortality/Morbidity

Literature describes pediatric mixed connective tissue disease from individual case reports to small series. Mortality is 0-50%. The review by Michels found a mortality figure of 7.6%.⁵ More recent data assess pediatric mortality at 3-4 per 1000 population versus adult mortality at 12-23 per 1000 population. Serious organ involvement included 47% of patients with renal disease, 54% with restrictive lung disease, and 29% with GI disease. Although rare, morbidity from cerebral disease, cardiomyopathy, myopericarditis, and pulmonary hypertension has been reported and is associated with a significant risk of mortality.

Race

Ethnic distribution for pediatric mixed connective tissue disease has not been reported. Literature suggests that no specific protection or propensity based on race is noted.

Sex

A female predominance, which is typical of other autoimmune diseases, is noted in mixed connective tissue disease. Three published series on pediatric mixed connective tissue disease report 89 of 105 patients to be female, or a female-to-male ratio of approximately 6:1.

Age

Age range for pediatric onset disease is younger than 16 years by definition. No specific age of onset is excluded. The median age at onset is 12 years, based on reported pediatric series. The youngest reported age at onset is 2 years. A recent 15-year retrospective study concluded the mean age at disease onset was 10.7 years.⁶

Clinical

History

• The most frequent presentation of mixed connective tissue disease (MCTD) is a child with polyarthritis, general malaise, and Raynaud phenomenon.
• Patients may present with the following:
  • Sclerodermatous skin (usually limited to fingers but can be more extensive).
  • Sausage-shaped fingers
  • Proximal muscle weakness
  • Rash (finger ulcers or pits, Gottren papules)
  • Vasculitic rashes (usually palpable purpuric rashes)
  • Dysphagia
  • Gastroesophageal reflux disease (GERD) symptoms
  • Fever
  • Rheumatoid nodules
  • Lymphadenopathy
  • Alopecia
  • Telangiectasia
  • Headache

Physical

Detailed physical examination is critical.

• Classification criteria other than autoantibody status rely on clinical examination and diagnostic tests.
• Consider the following to make the diagnosis:
  • Alopecia
  • Pleuritic chest pain
  • Pericardial rub
  • Arthritis
  • Raynaud phenomenon
  • Malar rash
  • Petechial rash
  • Muscle weakness
  • Swollen hands (especially dorsal surface)
  • Trigeminal neuropathy
  • Acrosclerosis or sclerodermatous skin changes
  • Epigastric tenderness

The following lists, published by several authors, are the criteria for making a diagnosis of mixed connective tissue disease:^1,2,3

• Sharp criteria
  • Definite diagnosis requires 4 major criteria with positive anti-U1 RNP greater than 1:4000 and a negative anti-Sm Ab. U1 RNP is the specific RNP protein associated with this syndrome.
  • Probable diagnosis requires either 3 major criteria or 2 major criteria (which must come from the first 3 major criteria listed) and 2 minor criteria plus an anti-U1 RNP greater than 1:1000.
  • Possible diagnosis requires 3 major criteria without serologic evidence of disease or, if anti-U1 RNP is greater than 1:100, 2 major criteria or 1 major and 3 minor criteria.
    • Major criteria include severe myositis, pulmonary involvement (diffusing capacity of lung for carbon monoxide 70% of normal, pulmonary hypertension, proliferating vascular lesions on lung biopsy), Raynaud phenomenon or esophageal hypomotility, swollen hands or sclerodactyly, and highest observed anti-U1 RNP (>1:10,000) with negative anti-Sm Ab.
    • Minor criteria include alopecia, leukopenia (4000 WBC/mL), anemia (<10 g/dL for females, <12 g/dL for males), pleuritis, pericarditis, arthritis, trigeminal neuralgia, malar rash, thrombocytopenia (<100,000/mL), mild myositis, and history of swollen hands.
• Alarcon-Segovia and Villareal classification
  • Serologic criterion is a positive anti-RNP at a titer of 1:1600 or higher.
  • Clinical criteria (at least 3) are edema of the hands, Raynaud phenomenon (ie, 2 or 3 color changes), acrosclerosis, synovitis, and myositis (laboratory or biopsy evidence).
• Kasukawa criteria
  • Diagnosis requires the following 3 conditions: (1) positive in either 1 of 2 common symptoms, (2) positive anti-RNP antibody, and (3) positive in 1 or more findings in 2 of 3 disease categories of A, B, and C. The following are disease findings A, B, and C:
    • SLE-like conditions (polyarthritis, lymphadenopathy, facial erythema, pericarditis or pleuritis, leukopenia [<4000/mL], or thrombocytopenia [<100,000/mL])
    • Progressive systemic sclerosislike findings (sclerodactyly, pulmonary fibrosis, restrictive lung disease [vital capacity <80%] or reduced diffusion capacity [<70%], hypomotility, or dilation of the esophagus)
    • Polymyositislike findings (muscle weakness, increased serum level of myogenic enzymes [creatine kinase], myogenic pattern on electromyogram)
  • Common symptoms include Raynaud phenomenon and swollen fingers or hands.

Causes

Specific causes of mixed connective tissue disease remain undefined.⁷

• Research suggests that many factors, including genetics, hormones, and environment, contribute to development of autoimmune syndromes.
• As mentioned in the Introduction, the hallmark of mixed connective tissue disease is the presence of autoantibodies to U1 small nuclear ribonucleoproteins, in particular a 70-kDa U1 protein. During cell death or apoptosis, the 70-kDa protein is cleaved by caspase-3 into a small 40-kDa protein. Several research groups have described this apoptotic form.
• Specific anti-RNP autoantibodies that preferentially bind to the apoptotic form of the U1 protein have been demonstrated in a group of patients with mixed connective tissue disease (29 of 53 tested). Furthermore, the concentration of the autoantibody is high early in the disease and decreases over time, suggesting that it correlates or represents an inciting event in disease onset.

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