eMedicine Specialties > Rheumatology > Systemic Rheumatic Disease

Mixed Connective-Tissue Disease

Author: Robert W Hoffman, DO, FACP, FACR, Chief, Division of Rheumatology and Immunology, Professor, Departments of Medicine and Microbiology & Immunology, University of Miami
Coauthor(s): Eric L Greidinger, MD, Associate Professor, Department of Medicine, Division of Rheumatology and Immunology, University of Miami Miller School of Medicine, Miami Veterans Affairs Medical Center
Contributor Information and Disclosures

Updated: Aug 7, 2008

Introduction

Background

Mixed connective-tissue disease (MCTD) was first recognized by Sharp and colleagues (1972) among 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

MCTD has been more completely characterized in recent years and is now recognized to consist of the following core clinical and laboratory features: Raynaud phenomenon, swollen hands, arthritis/arthralgia, acrosclerosis, esophageal dysmotility, myositis, pulmonary hypertension, high level of anti–U1-RNP antibodies, and antibodies against U1-70 kd small nuclear ribonucleoprotein (snRNP).

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 the presence of 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/*152
  • 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 lupus

Frequency

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.

Mortality/Morbidity

  • Recent long-term outcome studies have established pulmonary hypertension as the most common disease-related cause of death.3
  • Immunoglobulin G (IgG) anticardiolipin antibodies are a marker for development of pulmonary hypertension.
  • Infections are a major cause of death.

Race

MCTD has been reported in all races. The clinical manifestations of MCTD are similar among various ethnic groups.

Sex

The female-to-male ratio of MCTD is approximately 10:1.

Age

The onset of MCTD can occur at any age but typically occurs in people aged 15-25 years.

Clinical

History

Manifestations of mixed connective-tissue disease (MCTD) can be protean. Most patients experience Raynaud phenomenon, arthralgia/arthritis, swollen hands, sclerodactyly or acrosclerosis, and mild myositis. The following may be revealed by history or physical examination:

  • Raynaud phenomenon (96% cumulatively, 74% at presentation)
  • Arthralgia/arthritis (96% cumulatively, 68% at presentation)
  • Esophageal hypomotility (66% cumulatively, 9% at presentation)
  • Pulmonary dysfunction (66% cumulatively, rare at presentation)
  • Swollen hands (66% cumulatively, 45% at presentation)
  • Myositis (51% cumulatively, 2% at presentation)
  • Rash (53% cumulatively, 13% at presentation)
  • Leukopenia (53% cumulatively, 9% at presentation)
  • Sclerodactyly (49% cumulatively, 11% at presentation)
  • Pleuritis/pericarditis (43% cumulatively, 19% at presentation)
  • Pulmonary hypertension (23% cumulatively, rare at presentation)

Physical

Physical examination is helpful in confirming or identifying features of MCTD. Seek the following features on examination:

  • Fever should prompt a careful search for infection. However, infection may be present in the absence of fever and is one of the primary disease-related causes of mortality and/or morbidity in MCTD. The use of corticosteroids and immunosuppressive agents further increases the risk of infection.4
  • Corticosteroids may mask serious intra-abdominal processes, including appendicitis, vasculitis, pancreatitis, and bowel perforation.
  • Cardiopulmonary symptoms or findings should prompt a careful evaluation for pulmonary hypertension.
  • Capillary microscopy can assist in finding sclerodermatous-type nailfold changes.
  • Severe Raynaud phenomenon may result in digital vascular infarcts and ulcerations.
  • Pericarditis may be occult and can progress rapidly to cardiac tamponade.
  • Trigeminal neuralgia is common in MCTD.
  • Secondary Sjögren syndrome occurs in 25% of patients with MCTD and may cause both ocular symptoms and oral dryness.

Causes

  • The fundamental cause of MCTD remains unknown. Autoimmunity to components of the U1-70 kd snRNP are a hallmark of disease. Anti-RNP antibodies can precede overt clinical manifestations of MCTD, but overt disease generally develops within one year of anti-RNP antibody induction.
  • The loss of T-lymphocyte and B-lymphocyte tolerance, due to (1) cryptic self-antigens, (2) abnormalities of apoptosis, or (3) molecular mimicry by infectious agents, and driven by U1-RNA-induced innate immune responses, are proposed current theories of pathogenesis.

More on Mixed Connective-Tissue Disease

Overview: Mixed Connective-Tissue Disease
Differential Diagnoses & Workup: Mixed Connective-Tissue Disease
Treatment & Medication: Mixed Connective-Tissue Disease
Follow-up: Mixed Connective-Tissue Disease
References
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References

  1. Sharp GC, Irvin WS, Tan EM, et al. Mixed connective tissue disease--an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. Feb 1972;52(2):148-59. [Medline].

  2. Hoffman RW, Rettenmaier LJ, Takeda Y, et al. Human autoantibodies against the 70-kd polypeptide of U1 small nuclear RNP are associated with HLA-DR4 among connective tissue disease patients. Arthritis Rheum. May 1990;33(5):666-73. [Medline].

  3. Burdt MA, Hoffman RW, Deutscher SL, et al. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum. May 1999;42(5):899-909. [Medline].

  4. Jais X, Launay D, Yaici A, et al. Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum. Feb 2008;58(2):521-31. [Medline].

  5. Alarcon-Segovia D, Villareal M. Classification and diagnostic criteria for mixed connective tissue disease. In: Kasukawa R, Sharp GC, eds. Mixed Connective Tissue Disease and Anti-Nuclear Antibodies. Amsterdam: Excerpta Medica; 1987:33-40.

  6. Greidinger EL, Zang Y, Jaimes K, et al. A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen. Arthritis Rheum. Feb 2006;54(2):661-9. [Medline].

  7. Hoffman RW. Undifferentiated and mixed connective tissue disease. In: Wallace D, Hahn B, eds. Dubois Systemic Lupus Erythematosus. Lippincott, P: In press.

  8. Hoffman RW. Mixed connective tissue disease, overlap syndromes and Sjogren's syndrome. In: Lahita RG, ed. Systemic Lupus Erythematosus. 4th ed. San Diego, Calif: Academic Press; 2004.

  9. Hoffman RW. T cells in the pathogenesis of systemic lupus erythematosus. Clin Immunol. Oct 2004;113(1):4-13. [Medline].

  10. Hoffman RW, Cassidy JT, Takeda Y, et al. U1-70-kd autoantibody-positive mixed connective tissue disease in children. A longitudinal clinical and serologic analysis. Arthritis Rheum. Nov 1993;36(11):1599-602. [Medline].

  11. Hoffman RW, Greidinger EL. Mixed connective tissue disease. Curr Opin Rheumatol. Sep 2000;12(5):386-90. [Medline].

  12. Maldonado ME, Perez M, Pignac-Kobinger J, et al. Clinical and immunologic manifestations of mixed connective tissue disease in a Miami population compared to a Midwestern US Caucasian population. J Rheumatol. Mar 2008;35(3):429-37. [Medline].

  13. Perkins K, Hoffman RW, Bezruczko N. A Rasch analysis for classification of systemic lupus erythematosus and mixed connective tissue disease. J Appl Meas. 2008;9(2):136-50. [Medline].

  14. Smolen JS, Steiner G. Mixed connective tissue disease: to be or not to be?. Arthritis Rheum. May 1998;41(5):768-77. [Medline].

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Further Reading

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Keywords

mixed connective-tissue disease, MCTD, arthritis, arthralgia, esophageal reflux, secondary pulmonary hypertension, Raynaud phenomenon, systemic lupus erythematosus, SLE, scleroderma, myositis, anti–U1-ribonucleoprotein, anti–U1-RNP, acrosclerosis, esophageal dysmotility, myositis, rheumatic disease, antibodies against U1-70 kd, small nuclear ribonucleoprotein, snRNP

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Contributor Information and Disclosures

Author

Robert W Hoffman, DO, FACP, FACR, Chief, Division of Rheumatology and Immunology, Professor, Departments of Medicine and Microbiology & Immunology, University of Miami
Robert W Hoffman, DO, FACP, FACR is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Physicians, American College of Rheumatology, and Clinical Immunology Society
Disclosure: Nothing to disclose.

Coauthor(s)

Eric L Greidinger, MD, Associate Professor, Department of Medicine, Division of Rheumatology and Immunology, University of Miami Miller School of Medicine, Miami Veterans Affairs Medical Center
Eric L Greidinger, MD is a member of the following medical societies: American College of Physicians and American College of Rheumatology
Disclosure: Nothing to disclose.

Medical Editor

Bryan L Martin, DO, Chief, Allergy Immunology Department, Walter Reed Army Medical Center; Associate Professor of Medicine and Pediatrics, Uniformed Services University of the Health Sciences; United States Army Consultant in Allergy Immunology and Immunizations
Bryan L Martin, DO is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Osteopathic Internists, American College of Physicians, American Medical Association, and American Osteopathic Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Elliot Goldberg, MD, Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine
Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa
Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; Merck, Amgen, Biogen, Zimmer, Wyeth, Johnson&Johnson, Stryker, Medtronic, Zimmer.Abbott,  Ownership interest Other; West Penn Allegheny Health System Consulting fee Consulting; Alpharma Honoraria Consulting; Proctor&Gamble Grant/research funds Independent contractor

 
 
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