Mixed Connective Tissue Disease: Overlap

Mixed connective tissue disease (MCTD) is an overlap autoimmune syndrome first described by Sharp in 1972, defined by the presence of high-titer anti-U1 ribonucleoprotein (anti-U1 RNP) antibodies in conjunction with clinical features spanning at least two of the following: systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis (PM), and rheumatoid arthritis (RA). The U1 RNP complex is a nuclear ribonucleoprotein involved in pre-mRNA splicing; autoantibodies against its 70-kDa, A, and C protein subunits drive immune complex formation, complement activation via the classical pathway, and T-cell-mediated tissue injury across multiple organ systems. The pathogenesis involves loss of immune tolerance to the U1 snRNP complex, leading to autoreactive CD4+ T-helper cells that provide help to autoreactive B cells, amplifying autoantibody production. Immune complexes deposit in small and medium-sized blood vessels, triggering endothelial injury and vasculopathy that accounts for the hallmark feature of Raynaud phenomenon. The initial clinical presentation typically includes Raynaud phenomenon with puffy, swollen fingers (sausage digits) that may progress to sclerodactyly as the scleroderma component evolves. Vascular endothelial injury and intimal proliferation in the pulmonary vasculature leads to pulmonary arterial...