Mixed Connective-Tissue Disease 

  • Author: Robert W Hoffman, DO, FACP, FACR; Chief Editor: Herbert S Diamond, MD   more...
 
Updated: Dec 1, 2011
 

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, 2]

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).[3, 4]

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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 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/*15[5]
  • 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
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Epidemiology

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.[6]
  • 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.

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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: Johnson & Johnson Grant/research funds Innate Immunity Research; Eli Lilly Intellectual property rights Lupus research

Specialty Editor Board

Bryan L Martin, DO  Associate Dean for Graduate Medical Education, Designated Institutional Official, Associate Medical Director, Director, Allergy Immunology Program, Professor of Medicine and Pediatrics, Ohio State University College of Medicine

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.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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.

Alex J Mechaber, MD, FACP  Senior Associate Dean for Undergraduate Medical Education, Associate Professor of 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  Adjunct Professor of Medicine, Division of Rheumatology, University of Pittsburgh 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: Merck Ownership interest Other; Smith Kline Ownership interest Other; Zimmer Ownership interest Other

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. Zandman-Goddard G, Solomon M, Rosman Z, Peeva E, Shoenfeld Y. Environment and lupus related diseases. Lupus. Nov 7 2011;[Medline].

  3. Yoshida S. Pulmonary arterial hypertension in connective tissue diseases. Allergol Int. Nov 2011;60(4):405-9. [Medline].

  4. Cappelli S, Bellando Randone S, Martinovic D, Tamas MM, Pasalic K, Allanore Y, et al. "To Be or Not To Be," Ten Years After: Evidence for Mixed Connective Tissue Disease as a Distinct Entity. Semin Arthritis Rheum. Sep 27 2011;[Medline].

  5. 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].

  6. 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].

  7. 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].

  8. 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.

  9. 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].

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

  11. 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.

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

  13. 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].

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

  15. 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].

  16. 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].

  17. Schwemmle C, Kreipe HH, Witte T, Ptok M. Bamboo nodes associated with mixed connective tissue disease as a cause of hoarseness. Rheumatol Int. Nov 16 2011;[Medline].

  18. 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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