Introductory Remarks

Abstract

Starting from the first description of a cold-precipitable protein by Wintrobe and Buell in 1933, this chapter provides a synthetic chronological reconstruction of the main advances recorded in the study of mixed cryoglobulinemia (MC). Detailed accounts of its clinical features and structural heterogeneity appeared in the 1960s and in 1970s. These reports defined cryoglobulins as immune complexes most frequently consisting of a monoclonal IgM kappa, showing rheumatoid factor (RF) activity and endowed with the Wa cross-reactive idiotype, linked to polyclonal IgG. Following a rapidly disproved suggestion of HBV as an etiological agent in MC, a number of papers published from 1990 to 1994 firmly established that the large majority of MC patients are HCV-infected. More recently, B cell clonal expansion involving RF-secreting cells has been shown to be a common biological feature of MC, thus explaining the repeatedly observed progression from MC to overt non-Hodgkin's lymphoma (NHL), a phenomenon which seems, however, to be characterized by wide geographic variations. Pegylated interferon-α plus ribavirin has become the standard of care for HCV-positive MC patients, and the addition of rituximab, a chimeric anti-CD20 monoclonal antibody, has been shown to be clinically effective in a large proportion of patients with refractory or relapsing MC, as well as in HCV-positive patients with splenic lymphoma characterized by villous lymphocytes and in a few mostly low-grade NHLs. Hopefully, ongoing studies based on the administration of new protease inhibitors and new anti-CD20 monoclonal antibodies will further improve the therapeutic spectrum of MC.