The concept of
mixed connective tissue disease (
MCTD) as a separate
connective tissue disease (CTD) has persisted for more than four decades. High titers of
antibodies targeting the
U1 small nuclear ribonucleoprotein particle (
U1 snRNP) in peripheral blood are a sine qua non for the diagnosis of
MCTD, in addition to distinct clinical features including Raynaud's phenomenon (RP), "puffy hands,"
arthritis,
myositis,
pleuritis,
pericarditis,
interstitial lung disease (ILD), and
pulmonary hypertension (PH). Recently, population-based epidemiology data from Norway estimated the point prevalence of adult-onset
MCTD to be 3.8 per 100,000 and the mean annual incidence to be 2.1 per million per year, supporting the notion that
MCTD is the least common CTD. Little is known about the etiology of
MCTD, but recent genetic studies have confirmed that
MCTD is a strongly HLA (​human leukocyte
antigen)-linked disease, as the HLA profiles of
MCTD differ distinctly from the corresponding profiles of ethnically matched healthy controls and other
CTDs. In the first section of this review, we provide an update on the clinical, immunological, and genetic features of
MCTD and discuss the relationship between
MCTD and the other
CTDs. Then we proceed to discuss the recent advances in
therapy and our current understanding of prognosis and prognostic factors, especially those that are associated with the more serious pulmonary and cardiovascular complications of the disease. In the final section, we discuss some of the key, unresolved questions related to anti-RNP-associated diseases and indicate how these questions may be approached in future studies.