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Treatment of the mixed cryoglobulinemia syndrome

Fernando C Fervenza, MD, PhD
Michael D Leise, MD
Dario Roccatello, MD
Robert A Kyle, MD
Section Editors
Richard J Glassock, MD, MACP
Mark H Wener, MD
Deputy Editors
Albert Q Lam, MD
Monica Ramirez Curtis, MD, MPH


The mixed cryoglobulinemia syndrome is most often induced by hepatitis C virus (HCV) infection. It can also be associated with autoimmune or lymphoproliferative disorders or, rarely, can be idiopathic. Typically, it follows a chronic, smoldering course. Infrequently, mixed cryoglobulinemia may present with a rapidly progressive or even life-threatening course. (See "Overview of cryoglobulins and cryoglobulinemia" and "Clinical manifestations and diagnosis of the mixed cryoglobulinemia syndrome (essential mixed cryoglobulinemia)".)

The main indication for immunosuppressive therapy is progressive systemic disease affecting the kidneys, nervous system, gastrointestinal tract, skin, or digits. The prognosis is variable [1-6].

The treatment of patients with the mixed cryoglobulinemia syndrome will be reviewed here. An overview of cryoglobulinemia and a discussion of the clinical manifestations and diagnosis of the mixed cryoglobulinemia syndrome are provided elsewhere. (See "Overview of cryoglobulins and cryoglobulinemia" and "Clinical manifestations and diagnosis of the mixed cryoglobulinemia syndrome (essential mixed cryoglobulinemia)".)


Prior to the discovery of the association with hepatitis C virus (HCV), both prednisone and cytotoxic drugs (such as cyclophosphamide and chlorambucil) were often used in patients with mixed cryoglobulinemia. However, except in those patients with a rapidly progressive course, there was no clear evidence that these modalities were beneficial [3,4]. Rituximab has been gradually replacing cytotoxic drug therapy in such patients.

Rituximab is significantly more expensive than cyclophosphamide, and there are no data directly comparing rituximab with cyclophosphamide in these patients. Thus, cyclophosphamide should still be considered a therapeutic option in patients with mixed cryoglobulinemia, especially in life-threatening situations.

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Literature review current through: Dec 2017. | This topic last updated: Jan 06, 2016.
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