The term mixed connective tissue disease (MCTD) was coined by Sharp and coworkers in 1972 to distinguish the patients with combined clinical features of systemic lupus erythematosus (SLE), scleroderma or progressive systemic sclerosis (PSS), and polymyositis–dermatomyositis (PM–DM).<sup>62 Sharp G.C., Irvin W.S., Tan E.M. , e 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 : 148-159  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> Previously, clinicians have used various terminologies to describe the clinical disease in patients who demonstrate clinical features of more than one rheumatologic disease. The descriptive terms have included overlap syndrome, undifferentiated connective tissue disease, sclerodermatomyositis, rheumatoid arthritis and systemic lupus erythematosus (RUPUS), systemic lupus erythematosus and progressive systemic sclerosis or scleroderma (lupoderma), or mixed collagenosis.<sup>7 Bennett R.M. Mixed connective tissue disease and other overlap syndromes Textbook of Rheumatology Philadelphia: WB Saunders (1985).  1115-1136

Cliccare qui per andare alla sezione Riferimenti, 19 Ginsburg W.W., Conn D.L., Bunch T.W. , e al. Comparison of clinical and serologic markers in systemic lupus erythematosus and overlap syndrome: A review of 247 patients J Rheumatol 1983 ;  10 : 235-241

Cliccare qui per andare alla sezione Riferimenti</sup> Even though the concept of MCTD as a distinct clinical entity has been questioned, an international symposium on MCTD determined that, “on the basis of clinical, serologic, and immunologic data, MCTD seems to be a distinct entity.”<sup>3 Alarcon-Segovia D.A., Shiokawa Y. Chairmen's summary Mixed Connective Tissue Disease and Anti-Nuclear Antibodies Amsterdam: Elsevier Science Publishers B.V. (1987).  69

Cliccare qui per andare alla sezione Riferimenti</sup> Based on HLA type to predict differentiation of MCTD, some investigators have suggested that MCTD is, for most patients, an intermediate stage in a genetically determined progression to a recognized connective tissue disease, and those whose disease remains undifferentiated might be considered a distinct subset.<sup>17 Gendi N.S., Welsh Kl, Van Venrooij W.J. , e al. HLA type as a predictor of mixed connective tissue disease differentiation. Ten-year clinical and immunogenetic follow-up of 46 patients Arthritis Rheum 1995 ;  38 : 259-266  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> Furthermore, long-term follow-up of patients with the documented diagnosis of MCTD has shown that most patients with anti-(U1)snRNP antibodies have or will develop a classified connective tissue disease (SLE, PSS, or rheumatoid arthritis [RA]) within 5 years after clinical presentation.<sup>68 van den Hoogen F.H., Spronk P.E., Boerbooms A.M. , e al. Long-term follow-up of 46 patients with anti-(U1)snRNP antibodies Br J Rheumatol 1994 ;  33 : 1117-1120

Cliccare qui per andare alla sezione Riferimenti</sup> Other investigators have concluded that antibodies to RNAsmall nuclear ribonucleoprotein (snRNP) do not identify a particular subgroup within the overlap syndromes and that MCTD does not seem to be a distinct entity.<sup>38 Lazaro M.A., Maldonado-Cocco J.A., Catoggio L.J. , e al. Clinical and serologic characteristics of patients with overlap syndrome: Is mixed connective tissue disease a distinct clinical entity? Medicine 1989 ;  68 : 58-65

Cliccare qui per andare alla sezione Riferimenti</sup> These observations question the concept of MCTD being a distinct clinical entity.

A prerequisite for the diagnosis of MCTD is the presence of high titers of autoantibodies against uridinerich snRNP Ag.<sup>62 Sharp G.C., Irvin W.S., Tan E.M. , e 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 : 148-159  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> Sera containing snRNP are usually present in patients with MCTD, but are uncommon in patients with SLE, PSS, PM–DM, RA, or other rheumatologic diseases. The Sm antibodies and high titers of antinative DNA, detected in SLE, are uncommon in MCTD. In patients with MCTD, serum complement levels are usually normal or only slightly reduced and rheumatoid factor is present in more than half the patients.<sup>63 Sharp G.C., Singsen B.H. Mixed connective tissue disease Arthritis and Allied Conditions: A Textbook of Rheumatology Philadelphia: Lea and Febiger (1989).  1080-1091

Cliccare qui per andare alla sezione Riferimenti</sup> The characteristic laboratory abnormalities in MCTD include high titer (>1:1000) of speckled antinuclear antibodies (ANA), high levels of antibody to RNAse sensitive extractable nuclear antigen (ENA), and presence of snRNP antibody.<sup>63 Sharp G.C., Singsen B.H. Mixed connective tissue disease Arthritis and Allied Conditions: A Textbook of Rheumatology Philadelphia: Lea and Febiger (1989).  1080-1091

Cliccare qui per andare alla sezione Riferimenti</sup> The opinion that the presence of high titer of antibody to ENA and the absence of antibodies to Sm antigen are specific for MCTD has been debated.<sup>2 Alarcon-Segovia D., Palacios R. Human post-thymic precursor cells in health and disease. IV. Abnormalities in immunoregulatory T cell circuits in mixed connective tissue disease Arthritis Rheum 1981 ;  24 : 1486-1494  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> Furthermore, many patients who initially exhibit the specific ENA can become anti-snRNP and others originally diagnosed as having MCTD may subsequently demonstrate more classical clinical features of PSS or SLE.<sup>14 De-Clerck L.S., Meijers K.A., Cats A. Is MCTD a distinct entity? Comparison of clinical and laboratory findings in MCTD, SLE, PSS, and RA patients Clin Rheumatol 1989 ;  8 : 29-36

Cliccare qui per andare alla sezione Riferimenti</sup>

It is equally important to note that other prospective long-term studies of patients with MCTD have supported the concept of MCTD as a distinct entity.<sup>42 Lundberg I., Nyman U., Pettersson I. , e al. Clinical manifestations and anti-(U1)snRNP antibodies: A prospective study of 29 anti-RNP antibody positive patients Br J Rheumatol 1992 ;  31 : 811-817

Cliccare qui per andare alla sezione Riferimenti</sup> It has been suggested that the concept of MCTD as a distinct disease entity is better replaced by the term undifferentiated autoimmune rheumatic/connective tissue disorder because many of these patients later convert into PSS or SLE, and some remain undifferentiated.<sup>9 Black C., Isenberg D.A. Mixed connective tissue disease: Goodbye to all that Br J Rheumatol 1992 ;  31 : 695-700

Cliccare qui per andare alla sezione Riferimenti</sup> A review of the literature indicates that many investigators in the field now consider MCTD a distinct entity.<sup>1 Alarcon-Segovia D. Mixed connective tissue disease a decade of growing pains J Rheumatol 1981 ;  8 : 535-540

Cliccare qui per andare alla sezione Riferimenti, 10 Calderon J., Rodriguez-Valverde V., Andrade S.S. , e al. Clinical profile of patients with antibodies to nuclear ribonucleoprotein Clin Rheumatol 1984 ;  3 : 483-492  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 13 Cunningham P.H., Andrews B.S., Davis J.S. Immune complexes in progressive systemic sclerosis and mixed connective tissue disease J Rheumatol 1980 ;  7 : 301-308

Cliccare qui per andare alla sezione Riferimenti, 27 Hoffbrand B.I. Mixed connective tissue disease [letter] British Medical Journal 1972 ;  4 : 790

Cliccare qui per andare alla sezione Riferimenti, 40 Lemmer J.P., Curry N.H., Mallory J.H. , e al. Clinical characteristics and course in patients with high titer antiRNP antibodies J Rheumatol 1982 ;  9 : 536-542

Cliccare qui per andare alla sezione Riferimenti, 41 LeRoy E.C., Maricq H.R., Kahaleh M.B. Undifferentiated connective tissue syndromes Arthritis Rheum 1980 ;  23 : 341-343  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 52 Reichlin M. Patterns of clinical disease associated with antibodies to nuclear ribonucleoprotein J Rheumatol 1978 ;  5 : 407-411

Cliccare qui per andare alla sezione Riferimenti, 53 Reichlin M. Problems in differentiating SLE and mixed connective tissue disease [editorial] N Engl J Med 1976 ;  295 : 1194-1195  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 56 Sharp G.C. AntinRNP and antiSm antibodies Arthritis Rheum 1982 ;  25 : 757-760  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 59 Sharp G.C., Anderson P.C. Current concepts in the classification of connective tissue diseases. Overlap syndromes and mixed connective tissue disease (MCTD) J Am Acad Dermatol 1980 ;  2 : 269-279  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> The various classification criteria suggested for the diagnosis of MCTD are shown in Table 1