Definition and diagnosis of mixed connective tissue disease
- Robert M Bennett, MD, FRCP, MACR
Robert M Bennett, MD, FRCP, MACR
- Professor of Medicine
- Oregon Health & Science University
Mixed connective tissue disease (MCTD) was originally defined in 1972 as a connective tissue disorder characterized by the presence of high titers of a distinctive autoantibody, now called anti-U1 ribonucleoprotein (RNP) (previously termed antibody to extractable nuclear antigens [anti-ENA]) . The central premise of the MCTD concept is that of an overlap syndrome associated with anti-U1 RNP antibodies that incorporates selected clinical features of systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma [SSc]), and polymyositis (PM) .
The definitive diagnosis of MCTD is often complicated by the fact that the overlapping features tend to occur sequentially . This confusion arises due to the overlap of the various diffuse connective tissue diseases (DCTD), as well as to changes in the underlying pathology of the illnesses.
The definition and diagnosis of mixed connective tissue disease are reviewed here. The clinical manifestations, prognosis, and treatment of the illness, as well as a detailed discussion of anti-U1 RNP antibodies, are presented separately. (See "Clinical manifestations of mixed connective tissue disease" and "Prognosis and treatment of mixed connective tissue disease" and "Anti-U1 RNP antibodies in mixed connective tissue disease".)
Five major diffuse connective tissue diseases (DCTD) exist according to classification schema: systemic lupus erythematosus (SLE); systemic sclerosis (scleroderma [SSc]); polymyositis (PM); dermatomyositis (DM); and rheumatoid arthritis (RA). A sixth disorder, Sjögren's syndrome, is commonly associated with each of these diseases but is called primary Sjögren's syndrome when it occurs alone.
The classical clinical descriptions of these disorders are well known, and most patients with well-differentiated disease are easily recognized. However, the definitive diagnosis of each of these disorders is based upon criteria derived from expert opinion; as such, the diagnostic criteria are updated from time to time, depending upon the relevance of contemporary research. Clinicians experienced in the clinical presentations of the connective tissue disorder often note that one autoimmune rheumatic disease seems to evolve into another over the course of several years . This occurs in about 25 percent of patients, who are then said to have an overlap syndrome . (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes".)
Subscribers log in hereLiterature review current through: Nov 2017. | This topic last updated: Jul 18, 2017.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 1972; 52:148.
- Bennett RM, O'Connell DJ. Mixed connective tisssue disease: a clinicopathologic study of 20 cases. Semin Arthritis Rheum 1980; 10:25.
- Bennett RM. Overlap Syndromes. In: Textbook of Rheumatology, 8th, WB Saunders Co, Philadelphia 2009. p.1381.
- Bodolay E, Csiki Z, Szekanecz Z, et al. Five-year follow-up of 665 Hungarian patients with undifferentiated connective tissue disease (UCTD). Clin Exp Rheumatol 2003; 21:313.
- Maddison PJ. Overlap syndromes and mixed connective tissue disease. Curr Opin Rheumatol 1991; 3:995.
- Mosca M, Tani C, Neri C, et al. Undifferentiated connective tissue diseases (UCTD). Autoimmun Rev 2006; 6:1.
- Jonsson J, Norberg R. Symptomatology and diagnosis in connective tissue disease. II. Evaluations and follow-up examinations in consequence of a speckled antinuclear immunofluorescence pattern. Scand J Rheumatol 1978; 7:229.
- Doria A, Ghirardello A, de Zambiasi P, et al. Japanese diagnostic criteria for mixed connective tissue disease in Caucasian patients. J Rheumatol 1992; 19:259.
- Kahn MF, Appelboom T. Syndrom de Sharp. In: Les maladies systemiques, 3rd, Kahn MF, Peltier AP, Meyer O, Piette JC (Eds), Flammarion, Paris 1991. p.545.
- Alarcon Segovia D, Villareal M. Classification and diagnostic criteria for mixed connective tissue disease. In: Mixed Connective Tissue Disease and Anti-nuclear Antibodies, Kasukawa R, Sharp G (Eds), Elsevier, Amsterdam 1987. p.33.
- Kasukawa R, Tojo T, Miyawaki S. Preliminary diagnostic criteria for classification of mixed connective tissue disease. In: Mixed Connective Tissue Disease and Antinuclear Antibodies, Kasukawa R, Sharp G (Eds), Elsevier, Amsterdam 1987. p.41.
- Alarcón-Segovia D, Cardiel MH. Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients. J Rheumatol 1989; 16:328.
- Aringer M, Steiner G, Smolen JS. Does mixed connective tissue disease exist? Yes. Rheum Dis Clin North Am 2005; 31:411.
- Cappelli S, Bellando Randone S, Martinović D, et al. "To be or not to be," ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum 2012; 41:589.
- Kashiwazaki S, Kondo H, Fukui T. features of anti-nRNP antibody positive patients. In: Mixed Connective Tissue Disease and Anti-nuclear Antibodies, Kasukawa R, Sharp G (Eds), Elsevier, Amsterdam 1987. p.261.
- LeRoy EC, Maricq HR, Kahaleh MB. Undifferentiated connective tissue syndromes. Arthritis Rheum 1980; 23:341.
- Bodolay E, Szegedi G. [Undifferentiated connective tissue disease]. Orv Hetil 2009; 150:867.
- Lundberg I, Nyman U, Pettersson I, Hedfors E. Clinical manifestations and anti-(U1)snRNP antibodies: a prospective study of 29 anti-RNP antibody positive patients. Br J Rheumatol 1992; 31:811.
- Greidinger EL, Hoffman RW. Autoantibodies in the pathogenesis of mixed connective tissue disease. Rheum Dis Clin North Am 2005; 31:437.
- Hojaili B, Barland P. Trigeminal neuralgia as the first manifestation of mixed connective tissue disorder. J Clin Rheumatol 2006; 12:145.
- O'Connell DJ, Bennett RM. Mixed connective tissue disease--clinical and radiological aspects of 20 cases. Br J Radiol 1977; 50:620.
- Hajas A, Szodoray P, Barath S, et al. Sensorineural hearing loss in patients with mixed connective tissue disease: immunological markers and cytokine levels. J Rheumatol 2009; 36:1930.
- Fujita Y, Fujii T, Nakashima R, et al. Aseptic meningitis in mixed connective tissue disease: cytokine and anti-U1RNP antibodies in cerebrospinal fluids from two different cases. Mod Rheumatol 2008; 18:184.
- Bhinder S, Harbour K, Majithia V. Transverse myelitis, a rare neurological manifestation of mixed connective tissue disease--a case report and a review of literature. Clin Rheumatol 2007; 26:445.
- Pope JE. Other manifestations of mixed connective tissue disease. Rheum Dis Clin North Am 2005; 31:519.
- Bennett RM, Spargo BH. Immune complex nephropathy in mixed connective tissue disease. Am J Med 1977; 63:534.
- Kitridou RC, Akmal M, Turkel SB, et al. Renal involvement in mixed connective tissue disease: a longitudinal clinicopathologic study. Semin Arthritis Rheum 1986; 16:135.
- Lambova SN, Kuzmanova SI. Raynaud's phenomenon in common rheumatic diseases. Folia Med (Plovdiv) 2006; 48:22.
- Peller JS, Gabor GT, Porter JM, Bennett RM. Angiographic findings in mixed connective tissue disease. Correlation with fingernail capillary photomicroscopy and digital photoplethysmography findings. Arthritis Rheum 1985; 28:768.
- Hassoun PM. Pulmonary arterial hypertension complicating connective tissue diseases. Semin Respir Crit Care Med 2009; 30:429.
- Bull TM, Fagan KA, Badesch DB. Pulmonary vascular manifestations of mixed connective tissue disease. Rheum Dis Clin North Am 2005; 31:451.
- Lundberg IE. The prognosis of mixed connective tissue disease. Rheum Dis Clin North Am 2005; 31:535.
- Bennett RM, O'Connell DJ. The arthritis of mixed connective tissue disease. Ann Rheum Dis 1978; 37:397.
- Mimura Y, Ihn H, Jinnin M, et al. Rheumatoid factor isotypes in mixed connective tissue disease. Clin Rheumatol 2006; 25:572.
- Yin G, Cen XM, Yang M, Xie QB. [Detecting anti-cyclic citrullinated peptide antibody in patients with connective tissue diseases]. Sichuan Da Xue Xue Bao Yi Xue Ban 2011; 42:374.
- Maddison PJ, Mogavero H, Reichlin M. Patterns of clinical disease associated with antibodies to nuclear ribonucleoprotein. J Rheumatol 1978; 5:407.
- Mesa A, Somarelli JA, Wu W, et al. Differential immunoglobulin class-mediated responses to components of the U1 small nuclear ribonucleoprotein particle in systemic lupus erythematosus and mixed connective tissue disease. Lupus 2013; 22:1371.
- Bennett RM, Bong DM, Spargo BH. Neuropsychiatric problems in mixed connective tissue disease. Am J Med 1978; 65:955.
- Bennett RM, O'Connell DJ. Gastrointestinal systemic sclerosis in mixed connective tissue disease. Arthritis Rheum 1979; 22:429.
- Hagen NA, Stevens JC, Michet CJ Jr. Trigeminal sensory neuropathy associated with connective tissue diseases. Neurology 1990; 40:891.
- Sharp GC, Irvin WS, May CM, et al. Association of antibodies to ribonucleoprotein and Sm antigens with mixed connective-tissue disease, systematic lupus erythematosus and other rheumatic diseases. N Engl J Med 1976; 295:1149.
- Bennett RM. Mixed connective tissue disease and other overlap syndromes. In: Textbook of Rheumatology, 7th, Kelley W, Harris EDJ, Ruddy SH, Sledge G (Eds), WB Saunders, Philadelphia 2004. p.1241.
- Greidinger EL, Hoffman RW. The appearance of U1 RNP antibody specificities in sequential autoimmune human antisera follows a characteristic order that implicates the U1-70 kd and B'/B proteins as predominant U1 RNP immunogens. Arthritis Rheum 2001; 44:368.
- Rettenmaier LJ, Sharp GC, Takeda Y, et al. U1-68KD-positive mixed connective tissue disease appears genetically distinct, within HLA from systemic lupus erythematosus. Arthritis Rheum 1989; 32:S39.
- Netter HJ, Guldner HH, Szostecki C, Will H. Major autoantigenic sites of the (U1) small nuclear ribonucleoprotein-specific 68-kDa protein. Scand J Immunol 1990; 32:163.
- McHugh N, James I, Maddison P. Clinical significance of antibodies to a 68 kDa U1RNP polypeptide in connective tissue disease. J Rheumatol 1990; 17:1320.
- Margaux J, Hayem G, Palazzo E, et al. Clinical usefulness of antibodies to U1snRNP proteins in mixed connective tissue disease and systemic lupus erythematosus. Rev Rhum Engl Ed 1998; 65:378.
- 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; 33:666.
- van den Hoogen FH, Spronk PE, Boerbooms AM, et al. Long-term follow-up of 46 patients with anti-(U1)snRNP antibodies. Br J Rheumatol 1994; 33:1117.
- Lundberg I, Hedfors E. Clinical course of patients with anti-RNP antibodies. A prospective study of 32 patients. J Rheumatol 1991; 18:1511.
- Gendi NS, Welsh KI, Van Venrooij WJ, et al. HLA type as a predictor of mixed connective tissue disease differentiation. Ten-year clinical and immunogenetic followup of 46 patients. Arthritis Rheum 1995; 38:259.
- Alexander EL, McNicholl J, Watson RM, et al. The immunogenetic relationship between anti-Ro(SS-A)/La(SS-B) antibody positive Sjögren's/lupus erythematosus overlap syndrome and the neonatal lupus syndrome. J Invest Dermatol 1989; 93:751.
- Ruuska P, Hämeenkorpi R, Forsberg S, et al. Differences in HLA antigens between patients with mixed connective tissue disease and systemic lupus erythematosus. Ann Rheum Dis 1992; 51:52.
- Arnett FC. HLA and autoimmunity in scleroderma (systemic sclerosis). Int Rev Immunol 1995; 12:107.
- Genth E, Zarnowski H, Mierau R, et al. HLA-DR4 and Gm(1,3;5,21) are associated with U1-nRNP antibody positive connective tissue disease. Ann Rheum Dis 1987; 46:189.
- Kuwana M, Okano Y, Kaburaki J, Inoko H. Clinical correlations with HLA type in Japanese patients with connective tissue disease and anti-U1 small nuclear RNP antibodies. Arthritis Rheum 1996; 39:938.