Cryoglobulinemia: Better Treatments With Brighter Outcomes

November 15, 2013
James R. Berenson, MD, FACP

Oncology, Oncology Vol 27 No 11, Volume 27, Issue 11

The outcome for patients with cryoglobulinemia has improved since the recognition that the condition is frequently associated with HCV and that elimination of this virus has therapeutic benefit for affected patients.

Cryoglobulinemia is an uncommon disorder that is often associated with other diseases, including those involving immunologic and viral etiologies.[1,2] It is characterized by the presence of immunoglobulins (Ig) that precipitate at temperatures below 37oC (98.6oF). This precipitation often results in deposition of these proteins in a variety of tissues, frequently leading to end-organ damage. The review by Retamozo and colleagues[3] provides a comprehensive overview of the etiology, pathogenesis, and clinical manifestations-as well as the treatment-of different types of cryoglobulinemia. These include a monoclonal Ig variety known as type I, as well as mixed cryoglobulinemias of type II (which consists of polyclonal IgG and monoclonal IgM) and type III (in which patients have a polyclonal IgM). The presence of cryoglobulins is called cryoglobulinemia and is much more common than its clinical manifestations; symptomatic cryoglobulinemia is referred to as “cryoglobulinemic disease.”

Type I cryoglobulinemia results from expansion of a single B-cell clone, which produces a monoclonal Ig with cryoglobulinemic properties.[2,4] Thus, this disorder is commonly associated with the antibody-producing plasma cell dyscrasias, including most commonly monoclonal gammopathy of undetermined significance (MGUS), and less commonly, multiple myeloma and Waldenström macroglobulinemia. The clinical manifestations of type I cryoglobulinemia are often related to vascular disease caused by the accumulation of the cryoglobulins and their precipitation in blood vessels. Most of these effects are observed in small vessels and manifest as cutaneous features, but renal and cardiac effects have also been observed. The goal of the management of type I cryoglobulinemia in the setting of malignant disease is to eliminate the malignant B-cell clone that is producing the offending Ig through the use of effective anticancer treatment. Patients with MGUS are often managed with glucocorticosteroids, although the anti–B-cell antibody rituximab has been used, as has plasmapheresis; bortezomib has been tried as well. Patients who have malignant B-cell disorders associated with cryoglobulin production may also require ongoing plasmapheresis to control the vascular manifestations of the disease that occur in the presence of even small amounts of monoclonal Ig that may remain following effective treatment of their malignancy. Despite these therapeutic measures, patients often experience ongoing problems, especially skin-related symptoms, but there may be deterioration of cardiac and renal function as well.

Mixed cryoglobulinemias of types II and III are much more heterogeneous in their etiology. In years past, an obvious cause of mixed cryoglobulinemia often could not be identified; this changed with the discovery, more than 2 decades ago, that hepatitis C virus (HCV) was the cause in most cases.[5] This discovery has led to more specific treatments to eliminate the infectious agent in those patients who are virally infected.[6] The exact pathogenesis accounting for the association with HCV infection has been recently determined and involves a viral protein–induced stimulation of liver and immune cells.[7,8] The cryoglobulinemic Igs bind the viral core proteins, leading to their precipitation. Also, the monoclonal IgM is capable of forming large complexes with IgG and complement. These immune complexes lead to vascular damage that, in turn, results in the frequent purpura, joint symptoms, and generalized weakness experienced by most patients. Many patients have kidney involvement (primarily glomerulonephritis), and more severe complications may occur in some cases, including gastrointestinal, pulmonary, and CNS involvement. The treatment of patients with virally associated mixed cryoglobulinemia has focused on combination therapy with antiviral drugs to eliminate the offending HCV and its associated cryoglobulinemic-inducing proteins. Most patients receive ribavirin along with pegylated interferon-alfa, and the majority have good responses.[9] Specific polymorphisms have recently been shown to predict responses to this therapy among patients who have mixed cryoglobulinemia associated with HCV infection.[10] Therapy with three-drug combinations has also been evaluated in clinical trials; early results have been promising in terms of efficacy, but significant side effects have been seen, especially reductions in blood cell counts.[11] Rituxumab has been used as well, with randomized trials demonstrating its superiority over other more traditional treatment approaches. However, treatment with rituxumab may be associated with a worsening of vascular problems. Overall, the outcome for patients with HCV-associated mixed cryoglobulinemia has improved over the past 2 decades, with deaths now being most commonly related to vasculitis.[5] A small minority of these patients develop B-cell lymphomas.[5]

Patients with mixed cryoglobulinemia that does not have an infectious etiology often have other autoimmune and malignant B-cell conditions, especially B-cell lymphoma. These patients experience clinical problems similar to those observed in patients with HCV-associated disease.[12] The most common causes of death in this patient population are infections (50%) and vascular-related problems (19%), with two-thirds surviving 10 years.[13] Often these patients have been treated with immunosuppression with glucocorticosteroids and a variety of other agents. Rituxumab alone and in combination with these other drugs has also been used to treat these patients; a retrospective analysis suggests that the use of rituxumab specifically with glucocorticosteroids is especially effective, although this therapy carries a high risk of severe infection.[12]

Overall, the outcome for patients with cryoglobulinemia has improved since the recognition that the condition is frequently associated with HCV and that elimination of this virus has therapeutic benefit for affected patients. The lives of patients with cryoglobulinemia have also been significantly improved by more effective therapies, including those that reduce the quantities of cryoglobulins via drugs such as rituximab, which reduce the number of B cells that produce the offending immunoglobulins, as well as better treatments of B-cell malignancies such as myeloma, Waldenström macroglobulinemia, and B-cell lymphoma.


Dr. Berenson has consulted for and has received honoraria, speaker fees, and research grants from Millennium Pharmaceuticals.


1. Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet. 2012;379:348-60.

2. Trejo O, Ramos-Casals M, García-Carrasco M, et al. Cryoglobulinemia: study of etiologic factors and clinical and immunologic features in 443 patients from a single center. Medicine (Baltimore). 2001;80:252-62.

3. Ratamozo S, Brito-Zerón P, Bosch X, et al. Cryoglobulinemic disease. Oncology (Williston Park). 2013;27:1098-1128.

4. Payet J, Livartowski J, Kavian N, et al. Type I cryoglobulinemia in multiple myeloma, a rare entity: analysis of clinical and biological characteristics of seven cases and review of the literature. Leuk Lymphoma. 2013;54:767-77.

5. Saadoun D, Landau DA, Calabrese LH, Cacoub PP. Hepatitis C-associated mixed cryoglobulinaemia: a crossroad between autoimmunity and lymphoproliferation. Rheumatology (Oxford). 2007;46:1234-42.

6. Retamozo S, Díaz-Lagares C, Bosch X, et al. Life-threatening cryoglobulinemic patients with hepatitis C: clinical description and outcome of 279 patients. Medicine (Baltimore). 2013 Aug 22. [Epub ahead of print]

7. Rosa D, Saletti G, De Gregorio E, et al. Activation of naïve B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C virus-associated B lymphocyte disorders. Proc Natl Acad Sci USA. 2005;102:18544-9.

8. Sansonno D, Dammacco F. Hepatitis C virus, cryoglobulinemia, and vasculitis: immune complex relations. Lancet Infect Dis 2005;5:227-36.

9. Saadoun D, Resche Rigon M, Sene D, et al. Rituximab plus Peg-interferon-alpha/ribavirin compared with Peg-interferon-alpha/ribavirin in hepatitis C-related mixed cryoglobulinemia. Blood. 2010;116:326-34.

10. Piluso A, Giannini C, Fognani E, et al. Value of IL28B genotyping in patients with HCV-related mixed cryoglobulinemia: results of a large, prospective study. J Viral Hepat. 2013;20:e107-14.

11. Saadoun D, Resche Rigon M, Thibault V, et al. Peg-IFNα/ribavirin/protease inhibitor combination in hepatitis C virus associated mixed cryoglobulinemia vasculitis: results at week 24. Ann Rheum Dis. 2013 Apr 20. [Epub ahead of print]

12. Terrier B, Krastinova E, Marie I, et al. Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey. Blood. 2012;119:5996-6004.

13. Terrier B, Carrat F, Krastinova E, et al. Prognostic factors of survival in patients with non-infectious mixed cryoglobulinaemia vasculitis: data from 242 cases included in the CryoVas survey. Ann Rheum Dis. 2013;72:374-80.

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