Mixed Connective-Tissue Disease

Updated: Sep 29, 2017
  • Author: Eric L Greidinger, MD; Chief Editor: Herbert S Diamond, MD  more...
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Overview

Practice Essentials

Mixed connective-tissue disease (MCTD) was first recognized by Sharp and colleagues (1972) in a group of patients with overlapping clinical features of systemic lupus erythematosus (SLE), scleroderma, and myositis, with the presence of a distinctive antibody against what now is known to be U1-ribonucleoprotein (RNP). [1, 2]

MCTD has been more completely characterized in recent years and is now recognized to consist of the following core clinical and laboratory features [3, 4] :

Nevertheless, whether MCTD is a distinct disease entity has been in question since shortly after its original description. A minority of authors continue to suggest that MCTD represents subgroups or early stages of disorders such as systemic lupus erythematosus (SLE) or systemic sclerosis, or an overlap syndrome. [6] Ciang and colleagues propose that MCTD would more accurately be termed undifferentiated autoimmune rheumatic disease. [7]

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Pathophysiology

Pathophysiologic abnormalities that are believed to play a role in MCTD include the following:

  • B-lymphocyte hyperactivity, resulting in high levels of anti–U1-RNP and anti–U1-70 kd autoantibodies
  • T-lymphocyte activation, with anti–U1-70 kd–reactive T lymphocytes circulating in the peripheral blood
  • Apoptotic modification of the U1-70 kd antigen
  • Immune response against apoptotically modified self-antigens
  • Genetic association with major histocompatibility genes human leukocyte antigen (HLA)–DRB1*04/*15 [8]
  • Vascular endothelial proliferation with widespread lymphocytic and plasmacytic infiltration of tissues
  • Activation of Toll-like receptors in a pattern that may differ from that of SLE

In a study of a nationwide MCTD cohort in Norway, Flåm and colleagues found that HLA-B*08 and DRB1*04:01 were risk alleles for MCTD, while DRB1*04:04, DRB1*13:01 and DRB1*13:02 were protective. Risk alleles for SLE, systemic sclerosis, and polymyositis/dermatomyositis were distinct from those for MCTD. [9]

Over time, some patients with MCTD also develop anti-Sm autoantibodies—an expansion of the autoimmune response known as epitope spreading. Escolà-Vergé reported that epitope spreading occurred in 13 (43%) of 40 patients with MCTD, mainly during the first 2 years after diagnosis.Compared with patients who did not have epitope spreading, patients Patients with epitope spreading had  significantly lower prevalence of skin sclerosis (0% vs. 44%, P = 0.004) and a higher prevalence of interstitial lung disease (46% vs. 15%, P = 0.05). [10]

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Etiology

The fundamental cause of MCTD remains unknown. Autoimmunity to components of the U1-70 kd snRNP is a hallmark of disease. Anti-RNP antibodies can precede overt clinical manifestations of MCTD, but overt disease generally develops within 1 year of anti-RNP antibody induction.

The loss of T-lymphocyte and B-lymphocyte tolerance, due to cryptic self-antigens, abnormalities of apoptosis, or molecular mimicry by infectious agents, and driven by U1-RNA-induced innate immune responses, are proposed current theories of pathogenesis.

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Epidemiology

Frequency

A population-based study from Olmsted County, Minnesota found that MCTD occurred in about 2 persons per 100,000 per year. Diagnosis was frequently delayed, with a median of 3.6 years elapsing from first symptom to fulfillment of diagnostic criteria. [11] A study in American Indian and Alaska Native adults found a  prevalence of 6.4 per 100,000 (95% confidence interval 2.8-12.8). [12]

A nationwide study of MCTD in Norway found a point prevalence of 3.8 per 100,000 adults and an annual incidence rate of  2.1 per million. [13] The prevalence of MCTD in Japan was estimated to be 2.7 per 100,000. [14]

Mortality/Morbidity

Long-term outcome studies have established pulmonary hypertension as the most common disease-related cause of death. [15] Immunoglobulin G (IgG) anticardiolipin antibodies are a marker for development of pulmonary hypertension. Infections are also a major cause of death.

Cardiac disease, most often pericarditis, is also common in MCTD patients, with prevalence estimates ranging from 13% to 65%. Other cardiac abnormalities include conduction abnormalities, pericardial effusion, mitral valve prolapse, diastolic dysfunction, and accelerated atherosclerosis. In three prospective studies with 13-15 years of follow-up, MCTD patients had an overall mortality rate of 10.4%, and 20% of these deaths were directly attributable to cardiac causes. [16]

Race-, Sex-, and Age-related Variances

MCTD has been reported in all races. The clinical manifestations of MCTD are similar among various ethnic groups; however, one study observed ethnic differences in the frequency of end-organ involvement. [17]

MCTD is far more common in females than in males. Estimates of the female-to-male ratio vary from approximately 3:1 to 16:1. [13, 14]

The onset of MCTD is typically at 15-25 years of age, but can occur at any age.

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Prognosis

Most patients with MCTD have a favorable outcome. Cases of MCTD with typical clinical or serologic features occasionally evolve into scleroderma, SLE, or another rheumatic disease.

Pulmonary hypertension is the most common disease-associated cause of death. Careful monitoring and aggressive treatment may improve the outcome of pulmonary hypertension.

United States

Careful epidemiological studies have not been performed in the United States. MCTD appears to be more prevalent than dermatomyositis (1-2 cases per 100,000 population) but is less prevalent than SLE (15-50 cases per 100,000 population).

International

In an epidemiological survey in Japan, MCTD has a reported prevalence of 2.7 cases per 100,000 population. More recently, a population-based study in Norway found the point prevalence rate to be 3.8 cases per 100,000 adult population, with a female-to-male ratio of 3.3. [18]

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