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Mixed Connective Tissue Disease (MCTD)

by Rula A. Hajj-ali, MD

Mixed connective tissue disease (MCTD) 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 phenomenon, 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 additional immunosuppressants.

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 phenomenon may precede other manifestations by years. Frequently, the first manifestations resemble early SLE, systemic sclerosis, polymyositis, or even RA. Many patients appear to have an undifferentiated connective tissue disease initially. The disease manifestations may progress and become widespread, and the clinical pattern changes over time.

Diffuse swelling of the hands is typical but not universal. 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 involvement (most commonly membranous nephropathy) occurs in about 25% of patients and is typically mild; severe involvement, with morbidity or mortality, is atypical for MCTD. The lungs are affected in up to 75% of patients with MCTD. Interstitial lung disease is the most common lung manifestation; pulmonary hypertension is a major cause of death. Heart failure can occur. Sjögren syndrome may develop. A trigeminal sensory neuropathy may be the presenting feature and is considered the most frequent CNS manifestation.

Diagnosis

  • Testing for antinuclear antibodies (ANA), antibodies to extractable nuclear antigen (antibodies to U1 ribonucleoprotein, or RNP), and Smith [Sm]) and anti-DNA antibodies

  • Organ involvement determined as clinically indicated

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

Tests for ANA and antibody to U1 RNP antigen are done first. Almost all patients have high titers (often > 1:1000) of fluorescent ANA that produce a speckled pattern. Antibodies to U1 RNP are usually present at very high titers (> 1:100,000). Antibodies to the ribonuclease-resistant Sm component of extractable nuclear antigen (anti-Sm antibodies) and to double-stranded DNA (negative in MCTD by definition) are measured to exclude other disorders.

Rheumatoid factors are frequently present, and titers may be high. The ESR is frequently elevated.

Pulmonary hypertension should be detected as early as possible. Further evaluation depends on symptoms and signs; manifestations of myositis, renal involvement, or pulmonary involvement prompt tests of those organs (eg, CK, MRI, electromyogram, or muscle biopsy for diagnosis of myositis).

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 or 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 or the dominant clinical phenotype. 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 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. Prophylaxis for opportunistic infections, such as Pneumocystis jirovecii, should be added if combination immunosuppressive therapy is used.

Key Points

  • MCTD most often resembles SLE, systemic sclerosis, and/or polymyositis.

  • Typically, ANA and antibodies to U1 RNP are present and anti-Sm and anti-DNA antibodies are absent.

  • Anticipate pulmonary hypertension.

  • Treat mild disease with NSAIDs or antimalarials and more severe disease with corticosteroids and sometimes other immunosuppressants.

Drugs Mentioned In This Article

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  • RAYOS

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