Mixed connective tissue disease overview

Mixed connective tissue disease Microchapters

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Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Mixed connective tissue disease from other Diseases

Epidemiology and Demographics

Risk Factors

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Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Shaghayegh Habibi, M.D.[2]

## Overview

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MCTD was first defined by Gordon C.Sharp et al., in 1972. MCTD is a systemic autoimmune disease that is characterized by overlapping symptoms of two or more systemic autoimmune diseases (SLE, RA, DM, polymyositis, and scleroderma) and the presence of antibodies against U1snRNP. Primary pathogenesis in MCTD include vasculopathy leading to tissue ischemia, immunological and inflammatory processes and fibrosis caused by excessive synthesis of collagen and other proteins of matrix. In MCTD associated conditions include secondary Sjogren’s syndrome and trigeminal neuralgia. A significant association between U1RNP disease and HLA-DR4 and DR154-61 is detected It is an autoimmune disease and the exact cause is unknown. MCTD has to be differentiated from other conditions with similar presentation of arthritis and rash like systemic lupus erythematosus, rheumatoid arthritis, undifferentiated connective tissue disease, systemic sclerosis, Sjogren's syndrome, vasculitis, Behcet's syndrome, serum sickness, psoriatic arthritis and human parvovirus B19 infection. The incidence of MCTD is approximately 2.7 per 100,000 individuals per year and the mortality rate is nearly 10.4% over the period of 13-15 years. The female to male ratio is approximately 10 to 1. If the patients with MCTD left untreated, approximately 35% of patients may progress to develop lung fibrosis. Common complications of MCTD include polyarthritis, Raynaud's phenomenon, interstitial lung disease, esophageal dysmotility, sclerodactyly, polymyositis, and pulmonary hypertension. Major causes of morbidity in long-term MCTD patients include sclerodactyly, diffuse sclerosis, pulmonary arterial hypertension, and nervous system disease. Patients with MCTD may have a positive history of Raynaud’s phenomenon, arthralgia, gastroesophageal reflux, myalgia and dyspnea and common symptoms of MCTD include swollen fingers, diffuse swelling of hands, and dry cough. Physical examination is usually include tachycardia, tachypnea, periungual telangiectasia, sclerodactyly, jugular vein distention, rhonchi and wheezing, joint swelling and tenderness, and joints erythema and effusion. Laboratory findings consistent with the diagnosis of MCTD include antibodies against the U1RNP, rheumatoid factor (RF), high CRP levels, hypergammaglobulinemia, anemia, leucopenia, circulating immune complexes, and hypocomplementemia. An x-ray may be helpful in the diagnosis of complications of MCTD, which include features characteristic of polyarthritis and esophageal dilatation. The treatment of patients with MCTD depends on type of internal organ involvement, phase of the disease, and rate of disease progression. Treatment strategies must follow conventional treatments that are used for similar problems in other rheumatic diseases. Usually the treatment of patients with MCTD include low doses of steroids, NSAIDs, immunosuppressive drugs, and biologic agents. The treatment options in refractory cases or in severe clinical conditions include immunoglobulins, cytotoxic agents, and biologic drugs.

## Historical Perspective

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MCTD was first defined by Gordon C.Sharp et al., in 1972. It has been the first rheumatic disease syndrome defined by a serologic test. In 1976, Alarcon-Segovia proposed criteria for classifying MCTD among all types of connective tissue diseases. It demonstrates the close association between MCTD and Sjogren's syndrome.

## Classification

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There is no established system for the classification of mixed connective tissue disease.

## Pathophysiology

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MCTD is a systemic autoimmune disease that is characterized by overlapping symptoms of two or more systemic autoimmune diseases (SLE, RA, DM, polymyositis, and scleroderma) and the presence of antibodies against U1snRNP. Primary pathogenesis in MCTD include vasculopathy leading to tissue ischemia, immunological and inflammatory processes and fibrosis caused by excessive synthesis of collagen and other proteins of matrix. In MCTD associated conditions include secondary Sjogren’s syndrome and trigeminal neuralgia. A significant association between U1RNP disease and HLA-DR4 and DR154-61 is detected. Gross pathology of skin may include photo-distributed erythematosus annular lesions, papulosquamous lesions, telangiectasia, and sclerodactyly and the skin histopathological findings include poor and lichenoid interface dermatitis and suprabasilar exocytosis around necrotic keratinocytes.

## Causes

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Mixed connective tissue disease is an autoimmune disease and the exact cause is unknown.

## Differentiating mixed connective tissue disease from Other Diseases

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MCTD has to be differentiated from other conditions with similar presentation of arthritis and rash like systemic lupus erythematosus, rheumatoid arthritis, rhupus, undifferentiated connective tissue disease, systemic sclerosis, Sjogren's syndrome, vasculitis, Behcet's syndrome, Kikuchi's disease, serum sickness, psoriatic arthritis and human parvovirus B19 infection.

## Epidemiology and Demographics

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The incidence of mixed connective tissue disease is approximately 2.7 per 100,000 individuals per year. A nationwide study on MCTD showed the prevalence of mixed connective tissue disease was 2.7 per 100,000 individuals in Japan and 3.8 per 100,000 individuals in Norway. In MCTD, the mortality rate is nearly 10.4% over the period of 13-15 years. It is usually diagnosed during childhood and is more frequent among black and Asian population. The female to male ratio is approximately 10 to 1.

## Risk Factors

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There are no established risk factors for mixed connective tissue diease.

## Screening

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There is insufficient evidence to recommend routine screening for mixed connective tissue disease.

## Natural History, Complications, and Prognosis

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If the patients with mixed connective tissue disease left untreated, approximately 35% of patients may progress to develop lung fibrosis. Common complications of MCTD include polyarthritis, Raynaud's phenomenon, interstitial lung disease, esophageal dysmotility, sclerodactyly, polymyositis, and pulmonary hypertension. Major causes of morbidity in long-term MCTD patients include sclerodactyly, diffuse sclerosis, pulmonary arterial hypertension, and nervous system disease. The presence of pulmonary involvement is associated with worst prognosis and high mortality rate.

## Diagnosis

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### Diagnostic Study of Choice

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The diagnostic criteria of Kasukawa include symptoms common to all the diseases involved, presence of antibodies against the U1snRNP, and selected symptoms typical of each of the particular component diseases separately (systemic lupus erythematosus, systemic sclerosis, polymyositis). The MCTD can be confirmed when there is at least one common symptom, positive antibodies reacting with U1RNP, and at least one symptom from each of the component diseases.

### History and Symptoms

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Patients with MCTD may have a positive history of Raynaud’s phenomenon, arthralgia, gastroesophageal reflux, myalgia and dyspnea. Common symptoms of MCTD include swollen fingers (“sausage digits”), diffuse swelling of hands, and dry cough. Less common symptoms include rashes, alopecia, mild fever, fatigue.

### Physical Examination

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Physical examination of patients with MCTD is usually remarkable by clinical features seen in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), dermatomyositis (DM), polymyositis, and scleroderma. Physical examination in patients with MCTD include tachycardia, tachypnea, periungual telangiectasia, sclerodactyly, jugular vein distention, rhonchi and wheezing, joint swelling and tenderness, and joints erythema and effusion.

### Laboratory Findings

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Laboratory findings consistent with the diagnosis of MCTD include antibodies against the U1RNP, rheumatoid factor (RF), high CRP levels, hypergammaglobulinemia, anemia, leucopenia, circulating immune complexes, and hypocomplementemia.

### Electrocardiogram

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There are no ECG findings associated with MCTD.

### X-ray

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An x-ray may be helpful in the diagnosis of complications of mixed connective tissue disease, which include features characteristic of polyarthritis (soft tissue atrophy, calcifications, distal interphalangeal joint erosions, juxta-articular osteoporosis, joint space narrowing, marginal erosions, joint deformities without erosions, and osteonecrosis) and interstitial lung disease (ground−glass opacities, peripheral reticular infiltrates, and small irregular opacities).

### Echocardiography and Ultrasound

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There are no ultrasound findings associated with mixed connective tissue disease.

### CT scan

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In MCTD, the tomographic images may show radiographic abnormalities related to interstitial lung disease and the presence of esophageal dilatation. Chest CT scan findings include ground glass opacities, irregularity of the interfaces between the peripheral pleura and aerated lung parenchyma, septal and non-septal lines, intralobular reticular opacities, bronchiolectasis or traction bronchiectasis, areas of cystic spaces (honeycombing), areas of decreased attenuation and air trapping on expiratory computed tomography.

### MRI

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Musculoskeletal MRI can identify and characterize subclinical synovial inflammation and joint damage with a greater precision than X-rays. Also cardiac MRI is complementary for diagnosing pulmonary arterial hypertension.

### Other Imaging Findings

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There are no other imaging findings associated with mixed connective tissue disease.

### Other Diagnostic Studies

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Pulmonary function test may be helpful in the diagnosis of interstitial lung disease as a complication of MCTD. Findings suggestive of interstitial lung disease include significantly lower DLCO values in the active pulmonary stage and restrictive ventilatory defect (reduction of FEV1 and total lung capacity).

## Treatment

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### Medical Therapy

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The treatment of patients with MCTD depends on type of internal organ involvement, phase of the disease, and rate of disease progression. Treatment strategies must follow conventional treatments that are used for similar problems in other rheumatic diseases (SLE, scleroderma, polymyositis). Usually the treatment of patients with MCTD include low doses of steroids, NSAIDs, immunosuppressive drugs, and biologic agents. The treatment options in refractory cases or in severe clinical conditions include immunoglobulins, cytotoxic agents, and biologic drugs.

### Surgery

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In MCTD, surgical options are the alternative for the patients who continue to progress in the disease related complications despite aggressive therapy. The surgical options include procedures like atrial septostomy and lung transplantation.

### Primary Prevention

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There are no established measures for the primary prevention of MCTD.

### Secondary Prevention

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In MCTD effective measures for the secondary prevention of Raynaud's disease include vasodilator therapies (such as calcium channel blockers), preventive approaches like avoidance of cold temperatures, smoking, and sympathomimetic agents and use of warm and protection techniques of fingers. Current strategies include Bosentan (endothelin receptor antagonist) as the recommended medication for the prevention of new digital ulcers.

## References

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