We searched Medline and Embase (from January, 1990, to January, 2011). We used the search term “cryoglobulinemia” in combination with “epidemiology”, “diagnosis”, “virus”, “cancer”, “autoimmune”, “pathogenesis”, “hyperviscosity”, “vasculitis”, “prognosis”, and “therapy”. We focused on publications from the past 10 years but also included commonly referenced and highly regarded older publications. We searched the reference lists of articles identified by this search strategy and selected those
SeminarThe cryoglobulinaemias
Section snippets
Definition and classification
Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures less than 37°C and redissolve after rewarming. Cryoglobulinaemia refers to the presence of cryoglobulins in serum. However, the terms cryoglobulinaemic disease or cryoglobulinaemic vasculitis are used to describe patients with symptoms related to the presence of cryoglobulins. Many patients with cryoglobulinaemia remain asymptomatic.1
The pathological nature of cryoglobulins was postulated in 1933, in a patient with
Infections
The discovery of the hepatitis C virus (HCV) in 19898 radically changed the focus of research from essential to HCV-related cryoglobulinaemia.9, 10 Ferri and colleagues11 confirmed the detection of circulating HCV-RNA in nearly 90% of Italian patients with mixed cryoglobulinaemia, although later studies found wide geographical variations.12, 13, 14, 15 HCV is predominantly associated with type II cryoglobulinaemia. The hepatitis B virus is reported to be associated with mixed cryoglobulinaemia.7
Epidemiology
The prevalence of cryoglobulinaemia remains unknown.34 Reasons include the careful laboratory technique needed to isolate and identify cryoglobulins and the absence of a standard clinical assessment of patients with possible cryoglobulinaemia. Even so, because HCV infects more than 170 million individuals worldwide, the number of patients at risk for the complications of mixed cryoglobulinaemia is substantial.
The prevalence of HCV infection in patients with mixed cryoglobulinaemia ranges from
Generation of cryoglobulins
Cryoglobulins are generated by the clonal expansion of B cells, in the context of either lymphoproliferative disorders or persistent immune stimulation triggered by chronic infections or autoimmune diseases.5, 7, 37 Types I and II cryoglobulinaemias result from the monoclonal expansion of a clone that can be overtly malignant (multiple myeloma), smouldering (Waldenström's macroglobulinaemia, plasmacytoid lymphoma), or indolent (as in monoclonal gammopathy of unknown significance). By contrast,
Clinical manifestations
The percentage of patients with circulating cryoglobulins who develop symptoms varies from 2% to 50%.7 The most common presentation, the triad of purpura, arthralgia, and weakness, is reported in 80% of patients at disease onset.7, 16 The development of cryoglobulinaemic symptoms is affected by age, underlying illness (such as HCV infection) and the characteristics of the cryoglobulins (type II subclass, high serum concentrations).7, 53
Cryoglobulin testing
There are no standardised or validated diagnostic or classification criteria for cryoglobulinaemic vasculitis.83 Diagnosis is based on clinical, laboratory, and histopathological data. For most patients, cryoglobulinaemic disease is diagnosed by the presence of typical organ involvement (mainly skin, kidney or peripheral nerve) and circulating cryoglobulins.
The diagnosis of cryoglobulinaemia requires demonstration of the presence of cryoglobulins in serum (panel 1). Appropriate sample
Outcome
The evolution of cryoglobulinaemic disease varies widely. Roughly half of patients have chronic disease with no involvement of vital organs. A third of patients have moderate-to-severe disease, with chronic renal failure or cirrhosis, and nearly 15% present with sudden life-threatening disease.16 Patients with cryoglobulinaemic disease have a worse 10-year survival rate compared with the rate in the general population.16, 55 Risk factors for poor outcomes include male sex, age more than 60
Conventional immunosuppression
Treatment should be modulated according to the underlying aetiopathogenesis (hyperviscosity vs vasculitis) and the severity of clinical presentation (figure 5).1, 93, 98, 105, 106 There are three broad strategies in the treatment of cryoglobulinaemia: conventional immunosuppression, antiviral treatments, and biological therapies (panel 2).
The immunosuppressive approaches used in cryoglobulinaemic vasculitis, based on high-dose glucocorticoids and cyclophosphamide, were derived mainly from
Future perspectives
A new era in our understanding of and therapeutic approach to cryoglobulinaemia began 20 years ago with the discovery of the HCV. The progressive introduction of antiviral therapies, with eradication of HCV currently regarded as the therapeutic gold standard, has improved survival rates.77, 134 However, many aspects of the disease remain unresolved.1 The causes of essential cryoglobulinaemia are not known. Disease management remains difficult in many patients, because many do not respond or are
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