Mixed connective tissue disease (MCTD) occurs worldwide and in all races, with a peak incidence in adolescence and the 20s. About 80% of people who have this disease are women. The cause of MCTD is unknown. In many patients, the disorder evolves into classic systemic sclerosis Systemic Sclerosis Systemic sclerosis is a rare chronic disease of unknown cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints, and internal organs (especially the esophagus... read more or systemic lupus erythematosus (SLE) Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more .
Symptoms and Signs of MCTD
Raynaud syndrome Raynaud Syndrome Raynaud syndrome is vasospasm of parts of the hand in response to cold or emotional stress, causing reversible discomfort and color changes (pallor, cyanosis, erythema, or a combination) in... read more (Raynaud phenomenon) may precede other manifestations by years. Frequently, the first manifestations resemble early SLE, systemic sclerosis, polymyositis, or even rheumatoid arthritis. 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.
Initial, 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 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 rheumatoid arthritis (eg, boutonnière and swan-neck deformities) may be present. Proximal muscle weakness with or without tenderness is common, typically among people who have elevated levels of muscle enzymes (eg, creatinine kinase).
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.
Diagnosis of MCTD
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 Diagnosis Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more , systemic sclerosis Systemic Sclerosis Systemic sclerosis is a rare chronic disease of unknown cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints, and internal organs (especially the esophagus... read more , or polymyositis Autoimmune Myositis Autoimmune myositis is characterized by inflammatory and degenerative changes in the muscles (polymyositis) or in the skin and muscles (dermatomyositis). Manifestations include symmetric weakness... read more .
Tests for ANA and antibody to U1 RNP antigen are done first. Almost all patients have high titers of fluorescent ANA that produce a speckled pattern. Antibodies to U1 RNP are present, usually at very high titers. 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. The presence of anti-RNP antibodies is not sufficient to make the diagnosis of MCTD; typical clinical findings are also required.
Rheumatoid factors are frequently present, and titers may be high. The erythrocyte sedimentation rate is frequently elevated.
Pulmonary hypertension Diagnosis Pulmonary hypertension is increased pressure in the pulmonary circulation. It has many secondary causes; some cases are idiopathic. In pulmonary hypertension, pulmonary vessels become constricted... read more should be detected as early as possible with pulmonary function testing and echocardiography. Further evaluation depends on symptoms and signs; manifestations of myositis, renal involvement, or pulmonary involvement prompt tests of those organs.
Creatinine kinase, MRI, electromyogram, or muscle biopsy can help diagnose autoimmune myositis Diagnosis Autoimmune myositis is characterized by inflammatory and degenerative changes in the muscles (polymyositis) or in the skin and muscles (dermatomyositis). Manifestations include symmetric weakness... read more .
Prognosis for MCTD
The overall 10-year survival rate is about 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, myocardial infarction, colonic perforation, disseminated infection, and cerebral hemorrhage. Some patients have sustained remissions for many years without treatment.
Treatment of MCTD
Nonsteroidal anti-inflammatory drugs (NSAIDs) or antimalarials (eg, hydroxychloroquine, chloroquine) for mild disease
Corticosteroids and other immunosuppressants (eg, methotrexate, azathioprine, mycophenolate mofetil) for moderate to severe disease
Calcium channel blockers (eg, nifedipine) and sometimes phosphodiesterase inhibitors (eg, tadalafil) for Raynaud syndrome
General management and initial drug therapy are tailored to the specific clinical problem and are similar to those of SLE Treatment Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more or the dominant clinical phenotype. Most patients with moderate or severe disease respond to corticosteroids, particularly if treated early, and other immunosuppressants (eg, methotrexate, azathioprine, mycophenolate mofetil). Mild disease is often controlled by NSAIDs, antimalarials (eg, hydroxychloroquine, chloroquine), or sometimes low-dose corticosteroids. Severe major organ involvement usually requires higher doses of corticosteroids (eg, oral prednisone 1 mg/kg once a day) and additional immunosuppressants. If patients develop features of myositis or systemic sclerosis, treatment is as for those diseases.
Patients with Raynaud syndrome should be treated based on their symptoms and as tolerated by their blood pressure with calcium channel blockers (eg, nifedipine) and phosphodiesterase inhibitors (eg, tadalafil).
All patients should be closely monitored for atherosclerosis Diagnosis Atherosclerosis is characterized by patchy intimal plaques (atheromas) that encroach on the lumen of medium-sized and large arteries. The plaques contain lipids, inflammatory cells, smooth muscle... read more . Patients on long-term corticosteroid therapy should receive osteoporosis prophylaxis Prevention Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more . Prophylaxis for opportunistic infections, such as Pneumocystis jirovecii (see prevention of Pneumocystis jirovecii pneumonia Prevention Pneumocystis jirovecii is a common cause of pneumonia in immunosuppressed patients, especially in those infected with human immunodeficiency virus (HIV) and in those receiving systemic... read more ), should be added if combination immunosuppressive therapy is used.
Some experts encourage screening for pulmonary hypertension on a periodic basis with pulmonary function testing and/or echocardiography every 1 to 2 years, depending on symptoms.
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, but the presence of anti-RNP antibodies is not sufficient to make the diagnosis.
Anticipate pulmonary hypertension.
Treat mild disease with NSAIDs or antimalarials and more severe disease with corticosteroids and other immunosuppressants.
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