eMedicine Specialties > Dermatology > Connective Tissue Diseases

Mixed Connective Tissue Disease

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Anna Sysa-Jedrzejowska, MD, PhD, Head, Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland; Anna Wozniacka, MD, PhD, Adjunct Lecturer, Department of Dermatology, Medical University of Lodz, Poland
Contributor Information and Disclosures

Updated: Oct 5, 2009

Introduction

Background

Mixed connective-tissue disease (MCTD) is a disorder with features of systemic sclerosis (SSc), lupus erythematosus, and polymyositis. U1-ribonucleoprotein (RNP) antibodies are a specific marker of the disease. MCTD is considered a distinct syndrome and should not be confused with other connective-tissue disease overlap syndromes with features of various connective-tissue diseases.¹ The course of MCTD is chronic and usually milder than other connective-tissue diseases.

Pathophysiology

A defining feature of mixed connective-tissue disease (MCTD) is the presence of antibodies against the U1-RNP complex, but other autoantibodies have also been described in MCTD. Some hypotheses implicate modified self-antigens and/or infectious agents in the pathogenesis of MCTD.

The pathogenesis of MCTD is not completely known. As with other connective-tissue diseases, MCTD is considered an autoimmune disease to which individuals who express specific HLA antigens such as human leukocyte antigens (HLA) HLA-DR4 or HLA-DQB1 are genetically predisposed. The frequency of HLA-DR4 in patients with MCTD is estimated to be 52%. Its strong HLA association with MCTD was further shown in the significantly increased frequency of the combination of HLA-B15 with HLA-DR4. Thus, the genetic background in patients with MCTD seems to be different from that in patients with systemic lupus erythematosus (SLE) or systemic sclerosis. This observation could partly explain the clinical differences between these diseases. The specific nature of the HLA associations that occur in patients with MCTD may vary depending on the ethnicity of the population studied.

Frequency

International

Mixed connective-tissue disease (MCTD) is uncommon worldwide.

Mortality/Morbidity

• The prognosis for patients with mixed connective-tissue disease (MCTD) is generally better than that of patients with systemic lupus erythematosus, systemic sclerosis, and dermatomyositis.
• About 4% of patients die, usually as a result of pulmonary hypertension, nephritis, myocarditis, or widespread vasculitis.
• In one case series, solid tumors developed in approximately 10% of patients.

Sex

• Women are affected by mixed connective-tissue disease (MCTD) more often than men.
• The female-to-male ratio is 4:1.

Age

• Mixed connective-tissue disease (MCTD) usually occurs in individuals aged 30-50 years.
• MCTD also affects children, in whom the course is more severe because cardiac and renal involvement are more common.
• MCTD-related thrombocytopenia, which is unusual in adults, may be marked in children.

Clinical

History

Usually, patients with mixed connective-tissue disease (MCTD) present with Raynaud phenomenon, which frequently represents the initial manifestation of the disease.² The decreasing frequency of attacks limits progressive vascular damage. The course of the entity is often mild, but the clinical appearance and the patient's complaints depend on the symptoms related to the specific forms of the connective-tissue disease most expressed in the individual patient.

During the course of the disease in some patients, the typical signs and symptoms of systemic lupus erythematosus develop and fulfill at least 4 of the American Rheumatism Association (ARA) criteria. In other patients, MCTD becomes systemic sclerosis that spreads to the face, scalp, and trunk, and the fingers become immobile, hard, and shiny.

Usually, patients with MCTD present with Raynaud phenomenon. Headaches may occur, and patients may report fatigue. While myalgia and arthralgia are important early symptoms of pediatric-onset MCTD,³ many adolescent girls report pain along with fatigue.⁴ Raynaud phenomenon should hasten evaluation. Capillary findings should also be evaluated because they may correlate with the development of scleroderma spectrum disorders.

Physical

Mixed connective-tissue disease (MCTD) findings at physical examination may include the following:

• Skin⁵
  • Raynaud phenomenon, sausage-shaped fingers, and swelling of the dorsa of the hands that never becomes sclerodactyly are the most typical features (see Media File 2).

• More than one half of patients have abnormal capillaries in the nail fold.
• Small-vessel vasculitis with palpable purpura is present in about 25% of patients. Occasionally, vascular disturbances may be severe and lead to peripheral gangrene and leg ulcers.
• Other skin manifestations are not universally expressed. Erythematous plaques similar to those seen in patients with chronic cutaneous (discoid) lupus erythematosus can be seen. Alopecia, facial erythema, periungual telangiectasia, and pigmentary disturbances can also occur. Painful dermal nodules may appear on the hands or elbows.
• Joints
  • About 60% of patients complain of arthralgia.
  • Arthritis without any visible joint deformation can occur.
  • Any joint may be involved.
  • Patients usually complain of morning stiffness.
• Muscles: Myalgia, myositis, and muscle weakness are common features.
• Gastrointestinal tract
  • Dysphagia and dysfunction of esophageal motility resemble that occurring in systemic sclerosis.
  • Other abnormalities of the gut include esophagitis, constipation, diarrhea, and malabsorption.⁶
  • Correlated pulmonary function data and high-resolution CT scan findings of interstitial lung disease in 50 consecutive patients with MCTD suggests but does not prove a strong association between esophageal motor dysfunction and interstitial lung disease.⁷
• Lungs
  • Pleuropulmonary manifestations are common. The incidence varies from 20-85%.
  • Pleuropulmonary complications include pleural effusion, interstitial pulmonary fibrosis, pulmonary arterial hypertension, pulmonary vasculitis, pulmonary thromboembolic phenomena, aspiration pneumonia, serositis, and hypoventilatory failure.
  • Interstitial lung disease was identified in juvenile MCTD in one quarter of patients studied by high-resolution CT scanning.⁸ In most of them, it was subtle and without clinical correlation.
• Kidneys
  • The incidence of renal involvement is only about 5%.
  • Nephritis is associated with a poor prognosis. In addition to myocarditis, pulmonary hypertension, and widespread vasculitis, nephritis is considered a common cause of death.
• Nervous system
  • Nervous system involvement is rare.
  • Aseptic meningitis, trigeminal neuropathy, and psychosis are the prominent neurologic features.
  • Sporadic cases with autonomic neuropathy are described.
• Heart⁹ : Cardiac involvement is often clinically insignificant, but the rate varies from 11-85% depending on patient selection and methods used to detect cardiac manifestations. Pericarditis, pulmonary hypertension, mitral valve prolapse, myocarditis, conduction disturbances, and abnormal left ventricular diastolic filling pattern are the most frequently observed problems.
• Lymph nodes: Lymph node enlargement is seldom a feature, but it may be present.

Causes

The cause of mixed connective-tissue disease (MCTD) is not completely known.

• HLA-DR4 is more common in patients with MCTD than in patients with other connective-tissue diseases (see Pathophysiology).
• A genetic predisposition is confirmed by reports of familial occurrence.

• Search for CME/CE on This Topic »

• Mixed Connective-Tissue Disease (Rheumatology)
• Mixed Connective Tissue Disease (Pediatrics: General Medicine)
• Chronic Renal Failure (Nephrology)
• Raynaud Phenomenon (Pediatrics: General Medicine)

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