eMedicine Specialties > Rheumatology > Systemic Rheumatic Disease
Mixed Connective-Tissue Disease
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.
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References
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].
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].
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].
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].
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.
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].
Hoffman RW. Undifferentiated and mixed connective tissue disease. In: Wallace D, Hahn B, eds. Dubois Systemic Lupus Erythematosus. Lippincott, P: In press.
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.
Hoffman RW. T cells in the pathogenesis of systemic lupus erythematosus. Clin Immunol. Oct 2004;113(1):4-13. [Medline].
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].
Hoffman RW, Greidinger EL. Mixed connective tissue disease. Curr Opin Rheumatol. Sep 2000;12(5):386-90. [Medline].
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].
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].
Smolen JS, Steiner G. Mixed connective tissue disease: to be or not to be?. Arthritis Rheum. May 1998;41(5):768-77. [Medline].
Further Reading
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
Overview: Mixed Connective-Tissue Disease