Mixed Connective-Tissue Disease (MCTD)

Updated: Dec 22, 2022
  • Author: Eric L Greidinger, MD; Chief Editor: Herbert S Diamond, MD  more...
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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] :

  • Swollen hands
  • Arthritis/arthralgia
  • Acrosclerosis
  • Esophageal dysmotility
  • Myositis
  • Lung fibrosis [5]
  • High level of anti–U1-RNP antibodies
  • Antibodies against U1-70 kd small nuclear ribonucleoprotein (snRNP)

Different classification and diagnostic criteria for MCTD have been developed. [6] These include the Alarcón-Segovia diagnostic criteria [7, 8]  and, more recently, a set of criteria from a Japanese multispecialty consensus panel. [9]  See DDx/Diagnostic Considerations.

Nevertheless, whether MCTD is a distinct disease entity has been in question since shortly after its original description. A minority of authors continues to suggest that MCTD would be better characterized as subgroups or early stages of disorders such as SLE or systemic sclerosis. [10]  Other authors propose that MCTD cases should not be distinguished from undifferentiated autoimmune rheumatic disease. [11, 12]  

The overall goals of therapy for MCTD are to control symptoms, to maintain function, and to reduce the risk of future disease consequences. Medical therapy targets control of disease activity in general and management of specific organ involvement, while monitoring for and mitigating the risks of complications either of the condition itself (eg, pulmonary hypertension, interstitial lung disease) or of its treatment (eg, infection).



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 [13]
  • Vascular endothelial pathology, including features of hyperproliferation and increased endothelial apoptosis [14]
  • Lymphocytic and plasmacytic infiltration of tissues
  • Activation of Toll-like receptors in a pattern that may differ from that of classic SLE
  • A strong Type I Interferon activation signature in circulating cells [15, 16, 17]

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. [18]

Oka and colleagues performed genotyping of HLA-DRB1 and -DQB1 in 116 Japanese MCTD patients and 413 controls and analyzed the genotype frequencies. The analysis showed that HLA-DRB1*04:01 and DRB1*09:01 were risk alleles for Japanese MCTD. DRB1*13:02 was also confirmed to be protective against MCTD in Japanese patients. [19]

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 with epitope spreading had a 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). [20]



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 and other danger signal sensors induced by end-organ injury, are proposed current theories of pathogenesis.

It is notable that the RNA component unique to the U1-small nuclear ribonucleoprotein, U1-RNA, is among the most prevalent RNAs present in cellular apoptotic debris, and that U1-RNA is an agonist for autoimmunity-associated endosomal Toll-lIke receptors, including TLR7 and TLR3. [21, 22] These observations promote the hypothesis that immune recognition of apoptotic debris may play a key role in the etiology of anti-RNP autoimmunity, as in MCTD.



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. [23] 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). [24]


In an epidemiologic survey in Japan, MCTD has a reported prevalence of 2.7 cases per 100,000 population. [25] 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. [26]  


Long-term outcome studies have established pulmonary hypertension as the most common disease-related cause of death. [27] 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. [28]

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. [29]

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. [26, 25]

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



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. [30]  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) 



Patient Education

Education about MCTD and its treatment is essential. Active participation in the decision-making process empowers patients in their own care. Education about disease decreases the risk of patients developing learned helplessness and improves functional outcomes. For patient education information, see What Is Mixed Connective Tissue Disease (MCTD)?.