Shining a Warm Light on Cryoglobulinemia

November 15, 2013

We recommend screening for cryoglobulinemia in all patients with HCV infection, livedo reticularis, vasculitic cutaneous ulcers, positive rheumatoid factor or rheumatoid vasculitis, membranoproliferative glomerulonephritis, or atypical Waldenström macroglobulinemia.

In this issue of ONCOLOGY, Dr. Ramos-Casals and his group review the classification of cryoglobulinemia, its association with underlying diseases, and common treatment paradigms.[1]

The finding of a circulating immunoglobulin (Ig) that is precipitated by cooling and redissolved by warming is itself the definition of cryoglobulinemia, but by convention, cryoglobulinemia more typically refers to the infrequent clinical syndrome of cryoglobulinemic vasculitis that manifests with some combination of cutaneous symptoms, neuropathy, renal dysfunction, and/or arthralgias. Since these symptoms are nonspecific, diagnosis is often delayed. The situation has been helped by widespread recognition of the prevalence of cryoglobulins in hepatitis C virus (HCV) infection, where they are detectable in up to 25% to 30% of cases[2]; however, an index of suspicion is still required to order cryoglobulin testing in non–HCV-infected patients. We recommend screening for cryoglobulinemia in all patients with HCV infection, livedo reticularis, vasculitic cutaneous ulcers, positive rheumatoid factor or rheumatoid vasculitis, membranoproliferative glomerulonephritis, or atypical Waldenström macroglobulinemia (WM) (Table).

When testing for cryoglobulinemia, neither serum protein electrophoresis (SPEP) nor serum immunofixation (IF) are adequate screening tests. In a review of cases at our institution, 30 of 50 SPEP tests were normal despite the presence of mixed cryoglobulins, and IF detected a monoclonal protein in only 22 of 45 samples due to the relatively low titer of cryoglobulins.[3] However, IF that is performed after redissolving the cryoprecipitate will yield the monoclonal IgM due to the concentrating effect of the precipitation process. Thus serum cooling studies are required to diagnose or rule out cryoglobulinemia; there are no other laboratory findings sensitive and specific enough to establish the diagnosis. Also bear in mind that the cryocrit does not correlate to the severity of symptoms and thus cannot be used to determine the timing of treatment.

While the presence of monoclonal IgM indicates the presence of a clonal lymphoplasmacytic cell population, most patients with symptomatic cryoglobulinemia will not have evidence of overt lymphoma. Therefore-and to distinguish it from overt WM-cryoglobulinemia is recognized as a variant of WM and is classified as an IgM-related disorder, along with cold agglutinin disease, amyloid light-chain (AL) amyloidosis, and IgM neuropathies.[4,5] To the practicing hematologist/oncologist, this classification is likely to suggest treatment paradigms that may be borrowed from WM to treat symptomatic cryoglobulinemia.

In most cases, cryoglobulinemia is asymptomatic, and no immediate therapy is warranted. When cryoglobulins are detected in a patient without HCV infection or other apparent etiology, we recommend thorough staging studies to rule out possible lymphoma. If treatment is indicated for symptomatic disease, then we agree with Dr. Ramos-Casals and colleagues that treatment should be directed at the underlying cause. In the cohort with HCV infection, large patient numbers will allow for studies of new antivirals and other therapies. For the cohort without HCV infection, we consider the recent report by Terrier et al on the use of corticosteroids and rituximab[6] as having established this approach as the de facto standard of care, especially given the established role of this regimen in WM.

For refractory disease we continue to use chemotherapy, usually cyclophosphamide and high-dose corticosteroids or fludarabine-based therapy.[7,8] If a patient has life-threatening vasculitis or renal failure, we continue to employ plasmapheresis to acutely lower the cryocrit while initiating high-dose corticosteroids, cyclophosphamide, and anti-CD20 therapy. Not surprisingly, cutaneous complications and arthralgias improve most readily with therapy, while improvement in renal function and reversal of nerve damage are less likely to occur.

Importantly, anti-CD20 therapy with rituximab has been reported in HCV-positive cryoglobulinemia without clinically significant exacerbations of the HCV infection. This is relevant-the recommendation to first treat with antiviral therapy notwithstanding-because HCV-induced cryoglobulinemia can persist even after the HCV has been suppressed.[2] Although superficially puzzling, this finding is consistent with the conception of cryoglobulinemia as a variant of WM, which is to say a low-grade lymphoma that, once established, should persist even after the inducing stimulus has been removed.

In their report of a recent experiment, Visentini and colleagues note that hepatic marginal-zone B cells undergo massive clonal expansion upon HCV infection, followed by functional exhaustion and proliferative anergy. While the autoreactive antibodies produced by marginal-zone B cells account for autoimmune diseases, the profile of CD21-low B cells in HCV-positive cryoglobulinemia is more consistent with the anergic population, suggesting that it is a mutational event in this latter population that leads to the establishment of the malignant clonal population, which then proliferates independent of the original stimulus.[9]


The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.


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

2. Dammacco F, Sansonno D. Therapy for hepatitis C virus–related cryoglobulinemic vasculitis. N Engl J Med. 2013;369:1035-45.

3. Bryce AH, Kyle RA, Dispenzieri A, Gertz MA. Natural history and therapy of 66 patients with mixed cryoglobulinemia. Am J Hematol. 2006;81:511-8.

4. Owen RG, Treon SP, Al-Katib A, et al. Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. Sem Oncol. 2003;30:110-15.

5. Stone MJ. Pathogenesis and morbidity of autoantibody syndromes in Waldenstrom's macroglobulinemia. Clin Lymph Myel Leukemia. 2011;11:157-59.

6. 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.

7. Saadoun D, Pineton de Chambrun M, Hermine O, et al. Using rituximab plus fludarabine and cyclophosphamide as a treatment for refractory mixed cryoglobulinemia associated with lymphoma. Arthritis Care Res. 2013;65:643-7.

8. Rosenstock JL, Stern L, Sherman WH, et al. Fludarabine treatment of cryoglobulinemic glomerulonephritis. Am J Kidney Dis. 2002;40:644-8.

9. Visentini M, Conti V, Cristofoletti C, et al. Clonal expansion and functional exhaustion of monoclonal marginal zone B cells in mixed cryoglobulinemia: the yin and yang of HCV-driven lymphoproliferation and autoimmunity. Autoimmun Rev. 2013;12:430-5.