Abstract
In the early 1970s, Sharp and colleagues described a series of patients in whom features of Systemic lupus erythematosis (SLE), scleroderma, and inflammatory myositis were found in association with autoantibodies to the U1-ribonucleoprotein (RNP) antigen (1). This syndrome complex was called mixed connective tissue disease (MCTD). Although several classification criteria for MCTD have been published, there remains no universally accepted definition of the condition (2–5). The existence of MCTD as a clinically, immunogenetically, and serologically distinct entity remains a subject of controversy. An excellent review of MCTD and the controversy surrounding its classification has recently been published (6). In support of the concept of MCTD, recent published data demonstrate the distinctive serologic associations of anti-U1-70kD-specific, anti-U1-RNA-specific, and anti-heteronuclear ribonucleoprotein (hnRNP) A2/RA33-specific antibodies with MCTD (7–9). Furthermore, the association of anti-RNP and/or MCTD with the genetic marker HLA-DR4 has been reported from studies done in a number of different countries (6,7,10,11). Finally, it would appear that the concept of MCTD is useful to the clinician regardless of the controversy over nomenclature, because MCTD identifies a group of patients in whom increased surveillance for specific end-organ manifestations may improve patient care (12).
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Sharp, G.C., W.S. Irvin, E.M. Tan, R.G. Gould, and H.R. Holman. 1972. Mixed connective tissue disease: an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am. J. Med. 52:148–159.
Sharp, G.C. 1987. Diagnostic criteria for classification of MCTD, in Mixed Connective Tissue Disease and Antinuclear Antibodies. R. Kasukawa and G.C. Sharp, editors. Elsevier, Amsterdam. 23–32.
Alarcon-Segovia, D. and M. Villareal. 1987. Classification and diagnostic criteria for mixed connective tissue disease, in Mixed Connective Tissue Disease and Antinuclear Antibodies. R. Kasukawa and G.C. Sharp, editors. Elsevier, Amsterdam. 33–40.
Kasukawa, R., T. Tojo, and S. Miyawaki. 1987. Preliminary diagnostic criteria for classification of mixed connective tissue disease, in Mixed Connective Tissue Disease and Antinuclear Antibodies. R. Kasukawa and G.C. Sharp, editors. Elsevier, Amsterdam. 41–47.
Porter, J.F., L.C. Kingsland, III, D.A.B. Lindberg, I. Shah, J.M. Benge, S.E. Hazelwood, et al. 1988. The AI/RHEUM knowledge-based computer consultant system in rheumatology: performance in the diagnosis of 59 connective tissue disease patients from Japan. Arthritis Rheum. 31:219–226.
Smolen, J.S. and G. Steiner. 1998. Mixed connective tissue disease: to be or not to be? Arthritis Rheum. 41:768–777.
Sharp, G.C. and R.W. Hoffman. 1999. Mixed connective tissue disease, overlap syndromes and Sjogren’s syndrome, in Systemic Lupus Erythematosus, 3rd ed. R.G. Lahita, editor. Academic Press, New York.
Hoffman, R.W. 2001. Mixed connective tissue disease, in Textbook of Nephrology, 4th ed. S.G. Massry and R.J. Glassock, editors, pp. 787–790.
Hoffman, R.W. and E.L. Greidinger. 2000. Mixed connective tissue disease. Curr. Opin. Rheum., 12:386–390.
Sharp, G.C. and R.W. Hoffman. 1995. Mixed connective tissue disease, in Connective Tissue Diseases. J. Belch and R. Zurier, editors. Chapman and Hall, London, pp. 151–178.
Hoffman, R.W. and G.C. Sharp. 1995. Is Anti-U1–70kD Autoantibody-positive connective tissue disease genetically distinct? J. Rheumatol. 22:586–589.
Burdt, M.A., R.W. Hoffman, S.L. Deutscher, G.S. Wang, J.C. Johnson, and G.C. Sharp. 1999. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum. 42:899–909.
Ramos-Niembro, F. and D. Alarcon-Segovia. 1978. Familial aspects of mixed connective tissue disease (MCTD). J. Rheumatol. 5:433–440.
Nyman, U., I. Lundberg, E. Hedfors, M. Wahern, and I. Pettersson. 1992. IgG and IgM antisn-RNP reactivity in sequentially obtained serum samples from patients with connective tissue diseases. Ann. Rheum. Dis. 51:1307–1312.
Holyst, M-M., D.L. Hill, S.O. Hoch, and R.W. Hoffman. 1997. Analysis of human T cell and B cell responses against U small nuclear ribonucleoprotein 70-kd, B, and D polypeptides among patients with systemic lupus erythematosus and mixed connective tissue disease. Arthritis Rheum. 40:1493–1503.
James, J.A., T. Gross, H. Scofield, and J.B. Harley. 1995. Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: Sm B/B’-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity. J. Exp. Med. 181:453–461.
Fatenejad, S., M. Bennett, J. Moslehi, and J. Craft. 1998. Influence of antigen organization on the development of lupus autoantibodies. Arthritis Rheum. 41:603–612.
Greidinger, E.L. and R.W. Hoffman. 1999. The U1–70kDa protein is often the first snRNP to which humoral immunity develops in patients with U1–70kDa antibodies. Arthritis Rheum. 42:5110 (Abstract).
Casciola-Rosen, L., F. Andrade, D. Ulanet, W.B. Wong, and A. Rosen, 1999. Cleavage by granzyme B is strongly predictive of autoantigen status: implications for initiation of autoimmunity. J. Exp. Med. 190:815–826.
Casciola-Rosen, L., F. Wigley, and A. Rosen. 1997. Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: Implications for pathogenesis. J. Exp. Med. 185: 71–79.
Utz, P.J. and P. Anderson. 1998. Posttranslational protein modifications, apoptosis, and the bypass of tolerance to autoantigens. Arthritis Rheum. 41:1152–1160.
Casciola-Rosen, L., A. Pluta, P. Plotz, K. Nagaraju, A. Cox, S. Morris, and A. Rosen. 1998. HPMS1 is a novel, frequently targeted myositis autoantigen which is cleaved by granzyme B but not by caspases during apoptosis. Arthritis Rheum. 41:S127 (Abstract).
Greidinger, E.L., Casciola-Rosen, L., Morris, S.A., Hoffman, R.W. and A. Rosen. 2000. Autoantibody recognition of distinctly modified forms of the U1–70kDa antigen are associated with different clinical disease manifestations. Arthritis Rheum. 43:881–888.
Hoffman, R.W., L.J. Rettenmaier, Y. Takeda, J.E. Hewett, I. Pettersson, U. Nyman, et al. 1990. Human autoantibodies against the 70-kd polypeptide of U1 small nuclear RNP are associated with HLA-DR4 among connective tissue disease patients. Arthritis Rheum. 33:666–673.
Kaneoka, H., K.C. Hsu, Y. Takeda, G.C. Sharp, and R.W. Hoffman. 1992. Molecular genetic analysis of HLA-DR and HLA-DQ genes among anti-U1–70kD autoantibody-positive connective tissue disease patients. Arthritis Rheum. 35:83–94.
Botto, M., C. Dell’Agnola, A.E. Bygrave, E.M. Thompson, H.T. Cook, F. Petry, et al. 1998. Homozygous Clq deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nature Genet. 19:56–59.
Herrmann, M., R.E. Voll, O.M. Zoller, M. Hagenhofer, B.B. Ponner, and J.R. Kalden. 1998. Impaired phagocytosis of apoptotic cell material by monocyte-derived machrophages from patients with systemic lupus erythematosus. Arthritis Rheum. 41:1241–1250.
Simon, L.S., A.L. Weaver, D.Y. Graham, A.J. Kivitz, P.E. Lipsky, R.C. Hubbard, et al. 1999. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 282:1921–1928.
Laine, L., S. Harper, T. Simon, R. Bath, J. Johanson, H. Schwartz, et al. 1999. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Gastroenterology 117:1002–1005.
Hosoda, Y., Y. Suzuki, M. Takano, T. Tojo, and M. Homma. 1987. Mixed connective tissue disease with pulmonary hypertension: a clinical and pathological study. J. Rheumatol. 14:826–830.
Nishimaki, T., S. Aotsuka, H. Kondo, K. Yamamoto, Y. Takasaki, M. Sumiya, and R. Yokohari. 1999. Immunological analysis of pulmonary hypertension in connective tissue diseases. J. Rheumatol. 26: 2357–2362.
Okawa-Takatsuji, M., S. Aotsuka, M. Fujinami, S. Uwatoko, M. Kinoshita, and M. Sumiya. 1999. Up-regulation of intercellular adhesion molecule-1 (ICAM-1), endothelial leucocyte adhesion molecule-1 (ELAM-1) and class II MHC molecules on pulmonary artery endothelial cells by antibodies against U 1-ribonucleoprotein. Clin. Exp. Immunol. 116:174–180.
Satoh, M., H.B. Richards, and W.H. Reeves. 1999. Pathogenesis of Autoantibody Production and Glomerulonephritis in Pristane-Treated Mice, in Lupus: Molecular and Cellular Pathogenesis, G.M. Kammer and G.C. Tsokos, editors. Humana Press, Totowa, NJ. 399–416.
Shustov, A., V. Rus, P. Nguyen, and C.S. Via. 1999. Murine Graft-vs-Host Disease, in Lupus: Molecular and Cellular Pathogenesis. G.M. Kammer and G.C. Tsokos, editors. Humana Press, Totowa, NJ. 140–151.
Kono, D.H. and A.N. Theofilopoulos. 1997. The genetics of murine systemic lupus erythematosus, in Dubois’ Systemic Lupus Erythematosus, 5th ed. D.J. Wallace and B.H. Hahn, editors. Williams Wilkins, Baltimore. 119–132.
Russell, P.J., J.D. Hicks, and F.M. Burnet. 1966. Cyclophosphamide treatment of mouse systemic lupus erythematosus. Lancet 1:1280–1284.
Daikh, D.I. and D. Wofsy. 1999. Treatment of systemic lupus erythematosus by selective inhibition of T cell function, in Lupus: Molecular and Cellular Pathogenesis. G.M. Kammer and G.C. Tsokos, editors. Humana Press, Totowa, NJ. 642–655.
Liang, B., R.J. Gee, M.J. Kashgarian, A.H. Sharpe, and M.J. Mamula. 1999. B7 costimulation in the development of lupus: autoimmunity arises either in the absence of B7.1/B7.2 or in the presence of anti-B7.1/B7.2 blocking antibodies. J. Immunol. 163:2322–2329.
Sutcliffe, N., T. Stoll, S. Pyke, and D.A. Isenberg. 1998. Functional disability and end organ damage in patients with systemic lupus erythematosus (SLE), SLE and Sjogren’s syndrome (SS), and primary SS. J. Rheumatol. 25:63–68.
Gladman, D.D., C.H. Goldsmith, M.B. Urowitz, P. Bacon, P. Fortin, E. Ginzler, et al. 2000. The systemic lupus international collaborating clinics/American College of Rheumatology (SLICC/ACR) Damage index for systemic lupus erythematosus international comparison. J. Rheumatol. 27:373–376.
Hendra, T.J. 1988. Failure of steroid and immunosuppressant therapy to halt progression of mixed connective tissue disease. Br. J. Clin. Pract. 42:256–257.
Dahl, M., A. Chalmers, J. Wade, D. Calverly, and B. Munt. 1992. Ten year survival of a patient with advancing pulmonary hypertension and mixed connective tissue disease treated with immunosuppressive therapy. J. Rheumatol. 19:1807–1809.
Furuya, T., T. Suzuki, N. Onoda, K. Tamura, K. Sato, H. Demura, and S. Kashiwazaki. 1992. Mixed connective tissue disease associated with protein losing enteropathy: successful treatment with intravenous cyclophosphamide therapy. Intern. Med. 31:1359–1362.
Pines, A., N. Kaplinsky, E. Goldhammer, and O. Bregman. 1982. Corticosteroid induced remission of oesophageal involvement in mixed connective tissue disease. Postgrad. Med. J. 58:297–298.
Cohen, L.E., I. Faske, and M.A. Greist. 1989. Prostaglandin infusion therapy for intermittent digital ischemia in a patient with mixed connective tissue disease. Case report and review of the literature. Am. Acad. Dermatol. 20:893–897.
Satoh, J., H. Imai, T. Yasuda, H. Wakui, A.B. Biura, and Y. Nakamoto. 1994. Sclerodermatous renal crisis in a patient with mixed connective tissue disease. Am. J. Kidney Dis. 24:215–218.
Badesch, D.B., V.F. Tapson, and M.D. McGoon. 2000. Continuous intravenous epoprostenol for pulmonary hypertension due to scleroderma spectrum disease: A randomized, controlled trial. Ann. Int. Med. 132:425–434.
Lahaye, I.E., P.E. Rogiers, J.M. Nagler, and R. Chappel. 1999. Vanishing pulmonary hypertension in mixed connective tissue disease. Clin. Rheumatol. 18:45–47.
Alpert, M.A., T.A. Pressly, V. Mukerji, C.R. Lambert, B. Mukerji, H. Panayiotou, and G.C. Sharp. 1991. Acute and long-term effects of nifedipine on pulmonary and systemic hemodynamics in patients with pulmonary hypertension associated with diffuse systemic sclerosis, the CREST syndrome and mixed connective tissue disease. Am. J. Cardiol. 68:1687–1691.
Alpert, M.A., T.A. Pressly, V. Mukerji, C.R. Lambert, and B. Mukerji. 1992. Short- and long-term hemodynamic effects of captopril in patients with pulmonary hypertension and selected connective tissue disease. Chest 102:1407–1412.
Limburg, A.J., A.J. Smit, and J.H. Kleibeuker. 1991. Effects of cisapride on the esophageal motor function of patients with progressive systemic sclerosis or mixed connective tissue disease. Digestion 49:156–160.
Perlemuter, G., P. Cacoub, S. Chaussade, B. Wechsler, D. Couturier, and J.C. Piette. 1999. Octreotide treatment of chronic intestinal pseudoobstruction secondary to connective tissue diseases. Arthritis Rheum. 42:1545–1549.
Gaches, F., A.S. Blanc, B. Couret, and E. Arlet-Suau. 1998. Digital necrosis and Sharp’s syndrome: the success of topical application of granulocyte/macrophage-colony stimulating factor in promoting healing after amputation of three toes. Br. J. Dermatol. 138:550–551.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Humana Press, Inc., Totowa, NJ
About this chapter
Cite this chapter
Hoffman, R.W., Greidinger, E.L. (2002). Mixed Connective Tissue Disease. In: Tsokos, G.C. (eds) Modern Therapeutics in Rheumatic Diseases. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-239-5_23
Download citation
DOI: https://doi.org/10.1007/978-1-59259-239-5_23
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-4684-9708-3
Online ISBN: 978-1-59259-239-5
eBook Packages: Springer Book Archive