Does Mixed Connective Tissue Disease Exist? Yes

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Is mixed connective tissue disease a useful concept?

There is little dispute that patients exist who present with clinical features of more than one classic rheumatic disease. In many cases, patients who have such overlap syndromes are defined as having an overlap between disease A and disease B (eg, between systemic lupus erythematosus [SLE] and rheumatoid arthritis [RA]). An occasional patient has a combination of several features, such as RA-like erosive arthritis, Raynaud's phenomenon, esophageal dysmotility and fibrosing lung disease that is

Typical disease manifestations in mixed connective tissue disease

Patients who are diagnosed as having MCTD are likely to suffer at some time from polyarthritis, myositis, Raynaud's phenomenon, puffy hands or mild sclerodactyly, interstitial lung disease, and esophageal dysmotility [2], [4], [9], [10], [11].

Musculoskeletal disease is common. Arthralgias or frank arthritis affect most patients who have a diagnosis of MCTD—50% to 70% are rheumatoid factor positive and about half suffer from an erosive arthritis [12], [13], [14], [15]. Myalgias are another

Diseases with features similar to mixed connective tissue disease

If MCTD is not a distinct disease, but is an early stage of another disease, it is particularly important to look at these other diseases, despite our limited insight into their pathogenesis. By definition, MCTD shares features with RA, SLE, SSc, and the inflammatory muscle diseases, as well as with undifferentiated connective tissue diseases (UCTDs).

RA is a good starting point because it generally is a well-defined disease entity. RA is characterized clinically by a symmetric polyarthritis

Genetic issues

MCTD is associated with the HLA-DR4, -DR1, and (less prominently) -DR2 molecules (Table 1) [40], [41], [42], [43], [44], [45], [46], [47]. In contrast, SLE mainly is associated with HLA-DR2 and DR3 [48], [49], whereas SSc shows an association with HLA-DR5 or -DR3 [50], [51], [52], [53] and PM/DM shows an association with HLA-DR3 [54], [55]. Thus, two conclusions can be drawn: (1) there is sufficient linkage disequilibrium with certain HLA class II molecules to suggest that patients who have

Serologic issues

The cardinal autoantibody in MCTD is directed against the U1-snRNP (one of the major components of the spliceosome), which, in addition to the common set of Smith (Sm) core proteins, is associated specifically with the three proteins, U1-A, U1-C, and U1-70K; all of these may be targeted by U1-snRNP–specific antibodies [1], [2]. The pathogenicity of U1-snRNP antibodies has not been proven, but clinical associations that were observed in patients who had SLE and SSc [57], [58] might be

Summary

Taken together, there are several good, solid arguments for the existence of MCTD as a specific disease entity. There are patients who have clinical features that do not allow them to be grouped with patients who have SLE, lcSSc, RA, or UCTD. These patients are likely to carry HLA-DR molecules that are not found commonly in SLE or SSc but are associated more often with RA. They also are likely to show a high titer autoantibody level to a largely specific portion of the U1-snRNP protein; among

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