Correspondence

Interferon for Hepatitis C Virus–Negative Type II Mixed Cryoglobulinemia

N Engl J Med 1998; 338:1386-1387May 7, 1998

Article

To the Editor:

Essential mixed cryoglobulinemia (type II) has turned out to be secondary to hepatitis C virus (HCV) infection in the large majority of patients.1 Interferon is now considered the treatment of choice.2-5 It is generally believed that the efficacy of interferon in patients with mixed cryoglobulinemia depends on the suppression of HCV viremia, since viral antigens seem to be a key factor in cryoprecipitates.1 As a corollary, interferon might be anticipated to be effective only in HCV-associated cryoglobulinemias. In contrast, we found that interferon was highly effective in two HCV-negative patients with true essential type II mixed cryoglobulinemia.

The patients, both of whom were women (29 and 70 years old), presented with symptomatic cryoglobulinemic vasculitis without underlying immunologic, infectious, or neoplastic diseases. Tests for HCV viremia (a reverse-transcriptase–polymerase-chain-reaction [RT-PCR] assay) and anti-HCV antibodies (third-generation assays) were consistently negative before therapy. Tests for the hepatotropic hepatitis A, B, G, and E viruses (RT-PCR or serologic assays) were also negative, and aminotransferase levels were normal.

Serum samples from the patients were also tested after the dissociation of immune complexes by acid treatment. We used samples obtained before therapy that had been stored frozen. The serum samples were treated with acetate buffer, pH 3.5, and IgG and were separated on a Sephacryl S-300 column, as described elsewhere.6 As a positive control, we similarly processed a serum sample from a patient with type II cryoglobulinemia who was positive for anti-HCV antibodies. The eluted IgG from the two patients did not react in a third-generation enzyme-linked immunosorbent assay for anti-HCV antibodies, whereas the eluted IgG from the anti-HCV–positive patient retained strong reactivity.

Both patients had severe cryoglobulinemic vasculitis with purpura and peripheral neuropathy, one had distal necrosis, and one had membranoproliferative glomerulonephritis. The cryocrit before therapy was 6 percent in one patient and 9 percent in the other.

Recombinant interferon alfa-2a (Roferon-A, Hoffmann–LaRoche, Basel, Switzerland) was administered at a dose of 3 million units per day for three months and 3 million units every other day for the subsequent nine months, a protocol adopted for HCV-associated cryoglobulinemia.2,4 Both patients had a complete clinical response, with the disappearance of serum cryoglobulins and all signs of cutaneous vasculitis and with the normalization of kidney-function results and urinary values in the patient with nephropathy. Both patients have remained in complete remission for more than two years since the withdrawal of therapy.

True essential mixed cryoglobulinemia without evidence of HCV infection, although rare,5 represents a therapeutic challenge, since in principle it should not be treated with interferon. Our findings warrant a trial with interferon in such cases. Also, our data support the previous suggestion2,4 that the immunomodulatory properties of interferon rather than its antiviral properties may significantly account for its efficacy in cryoglobulinemic vasculitis. We cannot, however, rule out the possibility that these patients were infected with an unidentified interferon-sensitive virus other than hepatitis A, B, C, D, or E.

Milvia Casato, M.D.
Bruno Lagana, M.D.
University of Rome “La Sapienza”, 00185 Rome, Italy

Leopoldo P. Pucillo, M.D.
Fatebenefratelli–San Pietro Hospital, 00189 Rome, Italy

Isabella Quinti, M.D.
University of Rome “La Sapienza”, 00185 Rome, Italy

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Citing Articles (8)

Citing Articles

1. 1

   Lisa Y. Xu, Edward M. Esparza, Milan J. Anadkat, Kimberley G. Crone, Richard D. Brasington. (2009) Cutaneous Manifestations of Vasculitis. Seminars in Arthritis and Rheumatism 38:5, 348-360
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   Clodoveo Ferri, Alessandro Antonelli, Maria Teresa Mascia, Marco Sebastiani, Poupak Fallahi, Daniela Ferrari, Marco Giunti, Stefano A. Pileri, Anna Linda Zignego. (2007) B-cells and mixed cryoglobulinemia. Autoimmunity Reviews 7:2, 114-120
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3. 3

   Chetan Mukhtyar, Antoni Chan, Raashid Luqmani. (2007) Update on the use of biologics in primary systemic vasculitides. Expert Review of Clinical Immunology 3:6, 901-911
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4. 4

   Clodoveo Ferri, Maria Teresa Mascia. (2006) Cryoglobulinemic vasculitis. Current Opinion in Internal Medicine 5:2, 173-182
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5. 5

   Cabot, Richard C.Harris, Nancy Lee, Shepard, Jo-Anne O., Ebeling, Sally H.Ellender, Stacey M.Peters, Christine C., Kay, Jonathan, McCluskey, Robert T., . (2005) Case 31-2005. New England Journal of Medicine 353:15, 1605-1613
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6. 6

   M. Casato, D. Lilli, G. Donato, M. Granata, V. Conti, G. Del Giudice, D. Rivanera, C. Scagnolari, G. Antonelli, M. Fiorilli. (2003) Occult hepatitis C virus infection in type II mixed cryoglobulinaemia. Journal of Viral Hepatitis 10:6, 455-459
   CrossRef

7. 7

   P. Lamprecht, A. Gause, W. L. Gross. (1999) Cryoglobulinemic vasculitis. Arthritis & Rheumatism 42:12, 2507-2516
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8. 8

   Angela Dispenzieri, Peter D. Gorevic. (1999) CRYOGLOBULINEMIA. Hematology/Oncology Clinics of North America 13:6, 1315-1349
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