Mixed cryoglobulinemias (type II and III)
The effectiveness of interferon-α (IFN-α) in the management of MC was recognised prior to the demonstration of its close relationship with the HCV. In 1987 in fact, Bonomo et al.  obtained a therapeutic response in 77% of patients treated with 3 MU day−1 IFN-α for three months. Two subsequent controlled studies [77,78] showed that 2 MU day−1 for one month and then on alternate days for 5 months, or 1·5 MU day−1 for one month followed by 3 MU three times a week for 23 weeks produced significant clinical effects and reduced the signs of cutaneous vasculitis.
Our group has conducted a controlled randomised trial with 3 mU three times a week for one year . This treatment reduced the activity of ‘HCV-correlated MC’ in about 50% of patients. Association of IFN-α with 16 mg prednisolone (PDN) on the non-IFN-α days did not increase the percentage of clinical responses (42%), but did induce an earlier and stable response, and thus delayed recurrences. These two effects may be due to PDN's modulation of the proinflammatory chemokines induced by IFN-α. Lastly, it has been shown that the frequency of the remissions PDN induces on its own is the same as that of a placebo.
The therapeutic effect of IFN-α is closely associated with inhibition of viral replication. Reduction of the HCV RNA to nonmeasurable levels usually precedes transaminase normalisation and reduction of the cryocrit. Inhibition of the virus by IFN-α presumably means that fewer antigens are available for the formation of immune complexes. In addition, there may be a more active clearance of such complexes by the reticuloendothelial system, one reason being improvement of liver cell function. Decreased production and release of IgM-RFs and improved T cell function combine to reduce cryoprecipitation.
By analogy with the treatment of chronic HCV infection, low HCV RNA levels alone are predictive of a favourable response to IFN. Other parameters, such as the cryocrit, the RF titre and the frequency of vasculitis spurts, are of no value in this respect. In terms of clinical response, the effectiveness of IFN-α in the treatment of ‘HCV-correlated MC’ is comparable to that observed in the management of active chronic disease of the liver without cryoglobulinemia .
The demonstration that mean HCV RNA levels are increased by treatment with PDN alone is of particular interest, as it suggests that corticosteroids favor replication of HCV as in other viral diseases.
The improvement achieved with IFN-α, however, is generally short-lived. About 80% of responders relapse within six months after its suspension. There is thus a need to establish the optimum doses and more effective protocols.
Few data are available with regard to the effectiveness of IFN-α plus ribavirin in the management of cryoglobulinemia. In the light of what has been said so far, it may reasonably be supposed that this combination enhances and improves the virological response as in patients with chronic HCV-correlated hepatitis without cryoglobulinemia [82,83]. Some information can be gathered from a study  showing that administration of the combination to 17 patients in relapse and 4 who had not responded to IFN-α resulted in a stable response in about 50% of those in relapse, but no improvement in the nonresponders. These results have been confirmed by a recent study , in that 7 out of 9 (78%) patients unresponsive to IFN-α achieved a good clinical response to combination therapy.
A new formulation of IFN, called ‘pegylated IFN-α’ (PEG-IFN-α), may offer significantly better results than the standard formulation . It is chemically modified by the covalent attachment of a branched methoxy polyethylene glycol moiety. It results in substantial changes in the metabolism of the drug, with prolongation of half-life to maintain effective levels in the blood, thus making feasible its administration once-a-week. This sustained action reduces the viral replication that occurs on days without treatment during the standard thrice-weekly regimen of unmodified IFN.
These studies certainly illustrate the utility of IFN-α. However, they do not show whether its efficacy also extends to other clinical features of this protean syndrome. Little is known, for example, about the responses of cryoglobulinemic patients with neuritic or nephropathic complications or active skin ulcers. Here, indeed, IFN might precipitate or aggravate renal failure and neuropathies and delay ulcer healing. It has been suggested that cryoglobulinemia-related ischemic lesions may worsen, presumably through a decrease in inflammation-induced angiogenesis. The antiangiogenic activity of IFN may delay the appropriate healing of ischemic lesions .
Corticosteroid boluses usually improve renal function values and have a significant effect on proteinuria, but do not alter disease progression percentages . The natural history of HCV-positive glomerulonephritis and its progression to chronic renal failure and dialysis are not yet clear. The evidence from renal transplant patients suggests that membranoproliferative glomerulonephritis recurs in most HCV-positive patients and immuno-mediated organ damage may thus be inferred [89,90].
Symptomatic, refractory mixed cryoglobulinemia should be considered as an indication for plasmapheresis. Indeed, cryofiltration apheresis represents an effective and selective way to remove cryoproteins . Improvement in MC-related symptoms can be achieved even without biochemical or virologic response. In combination with cytotoxic agents, it has been used in treating patients with rapidly progressive cryoglobulinemic membranoproliferative glomerulonephritis  and other severe symptoms, including demyelinating neuropathy .
Many questions still remain unanswered: how should approximately 5% of cryoglobulinemic patients unrelated to HCV infection be treated? HCV-unrelated MC represents a cohort of patients for whom the term ‘essential’ should be maintained. Recently, a role for HIV infection has been proposed . However, no stringent diagnostic criteria have been provided and the possible pathogenetic mechanisms of HIV must be confirmed. Thus, treatment of HCV-negative MC patients poses a considerable challenge. Interferon therapy should not be given as a first intention, because additional autoimmune disorders or exacerbation of cryoglobulinemic vasculitis may occur .
The main conclusion that can be drawn is that there are no available consensus guidelines concerning how and how often cryoglobulinemic patients should be treated. It is clear that the optimal therapeutic outcome lies in the primary prevention of hepatitis C acquisition.
Innnovative therapeutic strategies, applied in a large number of patients, will hopefully provide long-awaited solutions. In this context, good promises seem to derive from our preliminary results with the use of rituximab, a chimeric monoclonal antibody specifically directed to CD20 antigen. This treatment possibly represents a reasonable option in HCV-negative cryoglobulinemia (unpublished data).
Single cryoglobulinemias (type I)
As type I cryoglobulins are found almost exclusively, as we have already mentioned, in patients with malignant lymphoproliferative disorders (multiple myeloma, Waldenström's macroglobulinemia, chronic lymphocytic leukemia), their treatment is mainly directed at the underlying cause and usually includes the combination of alkylating agents (such as chlorambucil and melphalan) and prednisone. In these patients, especially in those with Waldenström's macroglobulinemia, an increased frequency of hyperviscosity syndrome has been described. They, indeed, benefit of plasma exchange treatment, which results in improvement of retinal vessels and sensory and motor neuropathy .