Cryoglobulinemia and cryoglobulinemic vasculitis: etiological aspects and pathophysiological associations

The term cryoglobulinemia (CG) is used when detecting serum immunoglobulins that reversibly precipitate and form a gel at a temperature below 37 °C and dissolve when the temperature rises above 37 °C. Type I CG consists of only one isotype or a subclass of monoclonal immunoglobulins, while types II and III are classified as mixed CG (MCG) that is primarily characterized by the presence of immunoglobulins G and M. Types II and II-III MCG can result in cryoglobulinemic vasculitis (CGV) more frequently, whereas type III can lead to this condition less frequently. The presence of type I cryoglobulins is always associated with B-cell lymphoproliferative diseases. On the contrary, type II or type III MCG is more commonly associated with systemic autoimmune diseases and chronic infections. Thus, hepatitis C virus infection contributes to the development of MCG in 80–90% of cases. CGV is considered a rare disease worldwide (<5 cases per 10,000 people in the general European and North American populations). Among autoimmune diseases, primary Sjögren's syndrome (Sjögren's disease), systemic lupus erythematosus, and rheumatoid arthritis are most often associated with MCG. The pathogenetic role of cryoglobulins in inducing vasculitis is associated with both leukocyte recruitment to the vessels and deposition of immune complexes, with complement system activation and microvascular damage. The pathogenesis of MCG is associated with B-cell lymphoproliferation, autoantibody production, immunoglobulin synthesis, rheumatoid factor activity and the subsequent formation of cryoprecipitated immune complexes in conjunction with ineffective cryoglobulin clearance by monocytes and/or macrophages. This review contains updated information on the epidemiology, etiology, and pathogenesis of CG, with particular emphasis on MCG and CGV