Mixed Connective-Tissue Disease (MCTD)

Updated: Nov 25, 2020
  • Author: Eric L Greidinger, MD; Chief Editor: Herbert S Diamond, MD  more...
  • Print
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 since been more completely characterized and is now recognized to consist of the following core clinical and laboratory features [3, 4] :

Four different classification and diagnostic criteria for MCTD have been developed. [6] For example, the Alarcón-Segovia diagnostic criteria consist of a positive anti–U1 RNP titer (>1:1600) and at least three of the following five clinical findings [7, 8, 9] :

  • Hand edema
  • Synovitis
  • Biologically or histologically proven myositis
  • Raynaud phenomenon
  • Acrosclerosis with or without proximal systemic sclerosis

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 SLE or systemic sclerosis, or an overlap syndrome. [10] Ciang and colleagues propose that MCTD would more accurately be termed undifferentiated autoimmune rheumatic disease. [11]  

The overall goal of therapy for MCTD is to control symptoms and to maintain function. Target medical therapy to specific organ involvement and extent of disease activity, and monitor for the development of complications (eg, pulmonary hypertension, infection).

Next:

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 [12]
  • 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. [13]

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). [14]

Previous
Next:

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.

Previous
Next:

Epidemiology

United States

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. [15] 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). [16]

International

In an epidemiological survey in Japan, MCTD has a reported prevalence of 2.7 cases per 100,000 population. [17] 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, and an annual incidence rate of  2.1 per million. [18]  

Mortality/Morbidity

Long-term outcome studies have established pulmonary hypertension as the most common disease-related cause of death. [19] 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. [20]

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. [21]

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. [18, 17]

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

Previous
Next:

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. 

A long-term observational nationwide cohort study from Norway found that interstitial lung disease (ILD) was present in 41% of MCTD patients and progressed in 19% of patients across the observation period of a mean of 6.4 years. [22] The following were the strongest predictors of ILD progression:

  • Male sex  (hazard ratio [HR] = 4.0, 95% confidence index [CI]: 1.4, 11.5; P = 0.011)
  • Presence of anti-ro52 antibodies (HR = 3.5, 95% CI: 1.2, 10.2; P = 0.023)
  • Elevated anti-RNP titer (HR 1.5, 95% CI: 1.1, 2.0; P = 0.008)
  • Absence of arthritis (HR = 0.2, 95% CI: 0.1, 0.6; P = 0.004) 

 

Previous