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Mixed Connective-Tissue Disease

  • Author: Eric L Greidinger, MD; Chief Editor: Herbert S Diamond, MD  more...
 
Updated: Jul 08, 2016
 

Background

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] :

  • Raynaud phenomenon
  • Swollen hands
  • Arthritis/arthralgia
  • Acrosclerosis
  • Esophageal dysmotility
  • Myositis
  • Lung fibrosis [5]
  • Pulmonary hypertension
  • High level of anti–U1-RNP antibodies
  • Antibodies against U1-70 kd small nuclear ribonucleoprotein (snRNP)
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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 [6]
  • 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.[7]

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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.[8]

Mortality/Morbidity

Long-term outcome studies have established pulmonary hypertension as the most common disease-related cause of death.[9] 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.[10]

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.[11]

The female-to-male ratio of MCTD is approximately 3:1.

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.[12]

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Contributor Information and Disclosures
Author

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, American College of Rheumatology

Disclosure: Received grant/research funds from Johnson & Johnson for innate immunity research; Received intellectual property rights from Eli Lilly for lupus research.

Specialty Editor Board

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

Disclosure: Received salary from Medscape for employment. for: Medscape.

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, American College of Rheumatology

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; 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, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

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, American Osteopathic Association

Disclosure: Nothing to disclose.

Acknowledgements

Robert W Hoffman, DO, FACP, FACR Chief, Division of Rheumatology and Immunology, Professor, Departments of Medicine and Microbiology & Immunology, University of Miami, Leonard M Miller School of Medicine

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.

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. 1972 Feb. 52(2):148-59. [Medline].

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

  3. Yoshida S. Pulmonary arterial hypertension in connective tissue diseases. Allergol Int. 2011 Nov. 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. 2011 Sep 27. [Medline].

  5. Gunnarsson R, El-Hage F, Aaløkken TM, Reiseter S, Lund MB, Garen T, et al. Associations between anti-Ro52 antibodies and lung fibrosis in mixed connective tissue disease. Rheumatology (Oxford). 2016 Jan. 55 (1):103-8. [Medline].

  6. 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. 1990 May. 33(5):666-73. [Medline].

  7. Flåm ST, Gunnarsson R, Garen T, Lie BA, Molberg O. The HLA profiles of mixed connective tissue disease differ distinctly from the profiles of clinically related connective tissue diseases. Rheumatology (Oxford). 2014 Sep 3. [Medline].

  8. Ungprasert P, Crowson CS, Chowdhary VR, Ernste FC, Moder KG, Matteson EL. Epidemiology of Mixed Connective Tissue Disease 1985-2014: A Population Based Study. Arthritis Care Res (Hoboken). 2016 Mar 4. [Medline].

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

  10. Ungprasert P, Wannarong T, Panichsillapakit T, Cheungpasitporn W, Thongprayoon C, Ahmed S, et al. Cardiac involvement in mixed connective tissue disease: a systematic review. Int J Cardiol. 2014 Feb 15. 171(3):326-30. [Medline].

  11. 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. 2008 Mar. 35(3):429-37. [Medline].

  12. Gunnarsson R, Molberg O, Gilboe IM, Gran JT. The prevalence and incidence of mixed connective tissue disease: a national multicentre survey of Norwegian patients. Ann Rheum Dis. 2011 Jun. 70(6):1047-51. [Medline].

  13. Szodoray P, Hajas A, Kardos L, et al. Distinct phenotypes in mixed connective tissue disease: subgroups and survival. Lupus. 2012 Nov. 21(13):1412-22. [Medline].

  14. 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. 2008 Feb. 58(2):521-31. [Medline].

  15. Amigues JM, Cantagrel A, Abbal M, Mazieres B. Comparative study of 4 diagnosis criteria sets for mixed connective tissue disease in patients with anti-RNP antibodies. Autoimmunity Group of the Hospitals of Toulouse. J Rheumatol. 1996 Dec. 23 (12):2055-62. [Medline].

  16. Alarcón-Segovia D, Cardiel MH. Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients. J Rheumatol. 1989 Mar. 16 (3):328-34. [Medline].

  17. Khanna D, Gladue H, Channick R, Chung L, Distler O, Furst DE, et al. Recommendations for screening and detection of connective tissue disease-associated pulmonary arterial hypertension. Arthritis Rheum. 2013 Dec. 65 (12):3194-201. [Medline].

  18. Kusunose K, Yamada H, Hotchi J, Bando M, Nishio S, Hirata Y, et al. Prediction of Future Overt Pulmonary Hypertension by 6-Min Walk Stress Echocardiography in Patients With Connective Tissue Disease. J Am Coll Cardiol. 2015 Jul 28. 66 (4):376-84. [Medline].

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

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

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

 
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Raynaud phenomenon is a common feature of mixed connective tissue disease.
Chest radiograph in a patient with pulmonary hypertension reveals enlarged pulmonary arteries.
 
 
 
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