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It is considered to be a rare disorder, but its true prevalence remains unknown. The disease is more common in Southern Europe than in Northern Europe or Northern America. The prevalence of ''essential'' mixed cryoglobulinemia (MC) has been reported as approximately 1:100,000 (with a female-to-male ratio of 3:1), but this term is now used to refer to only a minority of MC patients without an overt etiological agent.

Two types of MC have been described: type II and type III, based on their immunochemical properties. In type II, the cryoprecipitable immune-complexes are composed of monoclonal Ig M, the autoantibodies , and polyclonal IgGs, the autoantigens ; in type III, the immune-complexes are composed of both oligo-/polyclonal IgMs and polyclonal IgGs. Type I cryoglobulinemia involves monoclonal immunoglobulins of only one isotype and is a distinct disease. MC is characterized by variable organ involvement including skin lesions (orthostatic purpura, ulcers), chronic hepatitis, membranoproliferative glomerulonephritis, peripheral neuropathy, diffuse vasculitis, and, less frequently, interstitial lung involvement and endocrine disorders. Some patients may develop lymphatic and hepatic malignancies, usually as late complications. MC syndrome may be associated with numerous infectious or immunological diseases. When isolated, MC may represent a distinct disease, the so-called ''essential'' MC.

The etiopathogenesis of MC is not completely understood. Hepatitis C virus (HCV) infection has been suggested to play a causative role, with the contribution of genetic and/or environmental factors, in the majority of patients. Moreover, MC may be associated with other infectious agents or immunological disorders, such as human immunodeficiency virus (HIV) infection or primary Sjogren syndrome.

Diagnosis is based on clinical and laboratory findings. Circulating mixed cryoglobulins, low levels of complement component 4 and orthostatic skin purpura are the hallmarks of the disease. Leukocytoclastic vasculitis involving medium-sized and, more often, small-sized blood vessels is the typical pathological finding, easily detectable by means of skin biopsy of recent vasculitic lesions.

Differential diagnoses include a wide range of systemic, infectious and neoplastic disorders, mainly autoimmune hepatitis, primary Sjögren syndrome, B-cell lymphomas, and rheumatoid arthritis.

Treatment should be directed according to the underling etiopathogenesis. The first-line treatment of infection-related MC should with the most appropriate specific anti-infectious therapy (typically antivirals). Patients with an underlying lymphoproliferative or autoimmune disorder should receive appropriate disease-specific therapy. Use of immunomodifiers, immunosuppressors, corticosteroids, and/or plasmapheresis should be tailored to the patient according to the progression and severity of specific clinical manifestations, and may be used alone or in combination/sequence with antivirals. Use of immunomodifiers, immunosuppressor and plasmapheresis may play a major role in HCV-negative MC ('essential' MC syndrome) or in clinically active/relapsed MC that can be observed also after HCV eradication in some patients. Anti-CD20 (rituximab) is increasingly employed as an effective and safe treatment for major MC complications (nephropathy, neuropathy, severe vasculitis, etc.). Long-term monitoring is recommended in all MC patients to assure timely diagnosis and treatment of the life-threatening complications.

Disease persistence and relapse is more likely to be prevented when the clinical history of MC is considered along with early treatment and eradication of HCV. Similarly, timely treatment of more severe manifestations of the MC syndrome can prevent progression of organ damage. The overall prognosis is poorer in patients with renal disease, liver failure, lymphoproliferative disease and malignancies. In addition, MC type II (less frequently MC type III), particularly in patients with long-lasting disease, shows higher predisposition for the development of malignant B-cell lymphoma or other malignancies.