Page 254 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

228 Clodoveo Ferri, Dilia Giuggioli and Marco Sebastiani

that refer to the presence in the serum of one (monoclonal cryoglobulinemia) or more
immunoglobulins or mixed cryoglobulinemia (MC), which precipitate at temperatures below
37°C and redissolve on rewarming [1].

Nosology and Classification

Cryoglobulinemia is classified into three categories according to the immunoglobulin (Ig)
composition [1]. Type I cryoglobulinemia consists of singular isotypes or subclass of Ig
whereas types II and III MC contain IC composed respectively of polyclonal IgG,
autoantigens and monoclonal or polyclonal IgM autoantibodies, the latter of which contain
rheumatoid factor (RF) activity. Type II MC shows a microheterogeneous composition with
immunoblotting and two-dimensional polyacrylamide gel electrophoresis of oligoclonal IgM
or a mixture of polyclonal and monoclonal IgM [1-4]. This serological subset represents an
intermediate evolutionary state between type III and type II MC, so termed type II–III MC.
These findings are in agreement with recent molecular studies that show the presence of
oligoclonal B-lymphocyte proliferation in liver and bone marrow tissue from patients with
MC (1-6). Whereas cryoglobulinemia type I is often asymptomatic and usually associated
with well-known hematological disorders (1-6), MC occurs in diverse infectious and systemic
disorders and frequently presents as an isolated laboratory finding without clinical
significance. The mixed cryoglobulinemia syndrome (MCs) and CV are interchangeable
terms for the resultant distinctive small vessel vasculitis (SVV) related to
cryoglobulinemia [1-6].

Epidemiology

Cryoglobulinemic vasculitis is a rare disorder with marked heterogeneity in its
geographical distribution, and increased prevalence in Southern more than Northern Europe
or North America. The male to female ratio is 3:1 with the commonest age at onset of disease
in the fourth to fifth decades and in older age [1-5]. As a result of the clinical polymorphisms
of CV, the prevalence of single manifestation such as skin vasculitis, nephritis, chronic
hepatitis, and peripheral neuropathy vary largely among cohorts. The relationship of hepatitis
C virus (HCV) with cryoglobulinemia and CV has been examined in numerous cohorts [1, 4,
5]. Low levels of circulating MC are detectable in more than 50% of patients while overt CV
develops in approximately 5% of HCV-infected individuals [1, 8]. Considering the high
prevalence of HCV infection worldwide, an increasing number of patients with HCV-related
CV and extrahepatic manifestations are expected to occur particularly in underdeveloped
countries where HCV prevalence is increased relative to the general population [1, 4].
Essential MCs (EMCs) and CV so defined as the absence of a recognized triggering factor,
underlying systemic infectious or specific neoplastic disorder, occurs less frequently in
individuals of Southern European descent and in selected geographic areas where there is a
higher prevalence of HCV infection and CV [1, 4].

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