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Mixed connective tissue disease is an uncommon, specifically defined, overlap syndrome characterized by clinical features of SLE, systemic sclerosis, and polymyositis with very high titers of circulating antinuclear antibody to a ribonucleoprotein antigen. Hand swelling, Raynaud's syndrome, polyarthralgia, inflammatory myopathy, esophageal hypomotility, and pulmonary dysfunction are common. Diagnosis is by the combination of clinical features, antibodies to ribonucleoprotein, and absence of antibodies specific for other autoimmune diseases. Treatment varies with disease severity and organ involvement but usually includes corticosteroids and sometimes additional immunosuppressive drugs.

Mixed connective tissue disease (MCTD) occurs worldwide and in all races, with a peak incidence in the teens and 20s. About 80% of people who have this disease are women. The cause is unknown. In some patients, the disorder evolves into classic systemic sclerosis or SLE.

Symptoms and Signs

Raynaud's syndrome may precede other manifestations by years. Frequently, the first manifestations resemble early SLE, systemic sclerosis, polymyositis, dermatomyositis, or even RA. Whatever the initial manifestation, limited disease tends to progress and become widespread, and the clinical pattern changes over time.

The most frequent finding is swelling of the hands that eventually causes a sausage-like appearance of the fingers. Skin findings include lupus or dermatomyositis-like rashes. Diffuse systemic sclerosis–like skin changes and ischemic necrosis or ulceration of the fingertips may occasionally develop.

Almost all patients have polyarthralgias, and 75% have frank arthritis. Often the arthritis is nondeforming, but erosive changes and deformities similar to those in RA (eg, boutonnière and swan-neck deformities) may be present. Proximal muscle weakness with or without tenderness is common.

Renal disease occurs in about 10% and is often mild but occasionally causes morbidity or mortality. Sometimes pulmonary involvement is the most serious complication. Heart failure can occur. Sjögren's syndrome may develop. A trigeminal sensory neuropathy develops more frequently in MCTD than in other systemic autoimmune diseases. It may be the presenting feature and is considered the most frequent CNS manifestation.

Diagnosis

• Testing for antinuclear antibodies (ANA), extractable nuclear antigen (ENA), and ribonucleoprotein (RNP)
• Organ involvement determined as clinically indicated

MCTD should be suspected when additional overlapping features are present in patients appearing to have SLE, systemic sclerosis, polymyositis, or RA.

• Tests for ANA and antibody to ENA and RNP antigen are done first.
• If results of these tests are compatible with MCTD (eg, RNP antibodies very high, positive ANA), tests for rheumatoid factors, anti Jo-1 (anti -histidyl t-RNA synthetase), antibodies to the ribonuclease-resistant Smith (Sm) component of ENA, and double-stranded DNA are done to exclude other possible diagnoses.
• Further workup depends on symptoms and signs; manifestations of myositis, renal involvement, or pulmonary involvement prompt tests of those organs (eg, CPK, MRI, electromyogram, or muscle biopsy for diagnosis of myositis).

Almost all patients have high titers (often > 1:1000) of fluorescent ANA that produce a speckled pattern. Antibodies to ENA are usually present at very high titers (> 1:100,000). Antibody to RNP is present, whereas antibody to the ribonuclease-resistant Sm component of ENA is absent.

Rheumatoid factors are frequently positive, and titers are often high. The ESR is frequently elevated.

Prognosis

The overall 10-yr survival rate is 80%, but prognosis depends largely on which manifestations predominate. Patients with features of systemic sclerosis and polymyositis have a worse prognosis. Patients are at increased risk of atherosclerosis. Causes of death include pulmonary hypertension, renal failure, MI, colonic perforation, disseminated infection, and cerebral hemorrhage. Some patients have sustained remissions for many years without treatment.

Treatment

• NSAIDs, antimalarials for mild disease
• Corticosteroids for moderate to severe disease
• Sometimes other immunosuppressants

General management and initial drug therapy are tailored to the specific clinical problem and are similar to those of SLE. Most patients with moderate or severe disease respond to corticosteroids, particularly if treated early. Mild disease is often controlled by NSAIDs, antimalarials, or sometimes low-dose corticosteroids. Severe major organ involvement usually requires higher doses of corticosteroids (eg, prednisone Some Trade Names
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1 mg/kg po once/day) and additional immunosuppressants. If patients develop features of myositis or systemic sclerosis, treatment is as for those diseases.

All patients should be closely monitored for atherosclerosis. Patients on long-term corticosteroid therapy should receive osteoporosis prophylaxis.

Last full review/revision February 2008 by Rula A. Hajj-ali, MD

Content last modified February 2008