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Blood, 1 June 2008, Vol. 111, No. 11, pp. 5267. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gertz, M. Search for Related Content PubMed PubMed Citation Articles by Gertz, M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Comment on Saadoun et al, page 5334 Critiquing Cryos Morie Gertz MAYO CLINIC In this issue of Blood, Saadoun and colleauges report changes in lymphocyte subsets in cryoglobulinemia patients prior to and after anti-CD 20 therapy. Type II (mixed) cryoglobulin represents circulating immune complexes composed of a monoclonal IgM associated to a polyclonal IgG, which defines it as a rheumatoid factor.1 The cryoprecipitable immune complex can be found in the complete absence of clinical symptoms, but can deposit diffusely on endothelial surfaces, activate complement, and produce a systemic vasculitis syndrome. At the Mayo Clinic cryoglobulinemia accounts for 0.7% of monoclonal proteins seen over a 43-year period. However, only 29% of cryoglobulins were type II. Type I cryoglobulins are common incidental findings in patients with monoclonal gammopathy of uncertain significance and multiple myeloma; the majority are asymptomatic. The presence of monoclonal IgM implies that there is a clonal proliferation of lympho-plasmacytic cells in the bone marrow. Some of these infiltrations are at a level where they can be defined as lymphoplasmacytic lymphoma, but often, specialized techniques are required to detect the presence of the clonal cells in the marrow. At the Second International Workshop on Waldenstrom Macroglobulinemia, mixed cryoglobulinemia was defined as a syndrome distinct from Waldenström macroglobulinemia, falling into the category of an IgM-related disorder without symptoms due to tumor mass or a significant marrow infiltration.2 The immune complex was thought for many years to be triggered by an unknown antigen. However, in 1990, hepatitis C was recognized as an etiologic factor for type II cryoglobulinemia. The most common target organs for this immune complex vasculitis are the skin, nerves, kidney, and liver. Patients who manifest solely with cutaneous purpura may not require systemic therapy, as these are asymptomatic and are primarily of cosmetic concern. Renal involvement is the most urgent indication for intervention, because a glomerulopathy capable of producing nephrotic-range proteinuria and dialysis-dependent renal failure can occur. The typical renal lesion is membranoproliferative glomerulonephritis, and electron-dense deposits are found with intracapillary thrombi.3 The figure demonstrates a classic vasculitis ulcer associated with a type II cryoglobulin. In the presence of viral hepatitis, treatment with interferon plus ribavirin produces a response in over half of patients, but relapses are common.4 In severe vasculitis, corticosteroids are required because responses to interferon are delayed. Plasma exchange and alkylating agents have been used, but have generally been found to be ineffective. Rituximab therapy has been reported to be effective in type II cryoglobulinemia.5 Because the lymphoplasmacytic cells that are the source of the monoclonal IgM protein strongly express CD20, this is a logical choice and its effectiveness has been demonstrated in corticosteroid failures. In this issue of Blood, Saadoun and coworkers studied 21 patients and demonstrated that, before therapy, there were dramatic reductions in CD19+ cells, increased numbers of memory B cells, and a high number of lymphoplasmacytic cells, and demonstrate the ability of rituximab to bring these abnormalities back to the normal range. This partially explains the mechanism of action of rituximab and the pretreatment immune dysregulation that exists in these patients. View larger version (105K): [in this window] [in a new window]   Vasculitic ulcer in a patient with type II cryoglobulinemia. Reproduced from American Journal of Hematology, Vol. 77, No. 4, 2004, pages 329-330. Copyright 2004 Wiley-Liss, Inc. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons Inc.   Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Gertz MA. Cold agglutinin disease and cryoglobulinemia. Clin Lymphoma. 2005;5:290–293.[Medline] [Order article via Infotrieve] 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. Semin Oncol. 2003;30:110–115.[CrossRef][Medline] [Order article via Infotrieve] Roccatello D, Fornasieri A, Giachino O, et al. Multicenter study on hepatitis C virus-related cryoglobulinemic glomerulonephritis. Am J Kidney Dis. 2007;49:69–82.[CrossRef][Medline] [Order article via Infotrieve] Parise ER, de Oliveira AC, Ferraz ML, Pereira AB, Leite KR. Cryoglobulinemia in chronic hepatitis C: clinical aspects and response to treatment with interferon alpha and ribavirin. Rev Inst Med Trop Sao Paulo. 2007;49:67–72.[Medline] [Order article via Infotrieve] Rego TC, Massumoto CM, Batista RS, Moura LH, Soares LM, Gomes AP. The use of monoclonal antibody (rituximab) in the treatment of type II mixed cryoglobulinemia. Braz J Infect Dis. 2007;11:174–175.[Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis David Saadoun, Michelle Rosenzwajg, Dan Landau, Jean Charles Piette, David Klatzmann, and Patrice Cacoub Blood 2008 111: 5334-5341. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gertz, M. Search for Related Content PubMed PubMed Citation Articles by Gertz, M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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