Introductory Remarks

  • Franco Dammacco
  • Domenico Sansonno


Starting from the first description of a cold-precipitable protein by Wintrobe and Buell in 1933, this chapter provides a synthetic chronological reconstruction of the main advances recorded in the study of mixed cryoglobulinemia (MC). Detailed accounts of its clinical features and structural heterogeneity appeared in the 1960s and in 1970s. These reports defined cryoglobulins as immune complexes most frequently consisting of a monoclonal IgM kappa, showing rheumatoid factor (RF) activity and endowed with the Wa cross-reactive idiotype, linked to polyclonal IgG. Following a rapidly disproved suggestion of HBV as an etiological agent in MC, a number of papers published from 1990 to 1994 firmly established that the large majority of MC patients are HCV-infected. More recently, B cell clonal expansion involving RF-secreting cells has been shown to be a common biological feature of MC, thus explaining the repeatedly observed progression from MC to overt non-Hodgkin’s lymphoma (NHL), a phenomenon which seems, however, to be characterized by wide geographic variations. Pegylated interferon-α plus ribavirin has become the standard of care for HCV-positive MC patients, and the addition of rituximab, a chimeric anti-CD20 monoclonal antibody, has been shown to be clinically effective in a large proportion of patients with refractory or relapsing MC, as well as in HCV-positive patients with splenic lymphoma characterized by villous lymphocytes and in a few mostly low-grade NHLs. Hopefully, ongoing studies based on the administration of new protease inhibitors and new anti-CD20 monoclonal antibodies will further improve the therapeutic spectrum of MC.


Mixed Cryoglobulinemia Cryoglobulinemic Vasculitis Mixed Cryoglobulinemia Patient Cryoglobulinemic Patient 
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  1. 1.
    Wintrobe MM, Buell MV (1933) Hyperproteinemia associated with multiple myeloma with report of a case in which an extraordinary hyperproteinemia was associated with thrombosis on the retinal veins and symptoms suggesting Raynaud’s disease. Bull Johns Hopkins Hosp 52:156–165Google Scholar
  2. 2.
    Lerner AB, Watson CJ (1947) Studies of cryoglobulins. I. Unusual purpura associated with the presence of a high concentration of cryoglobulin (cold precipitable serum globulin). Am J Med Sci 214:410–415PubMedCrossRefGoogle Scholar
  3. 3.
    Lospalluto J, Dorward B, Miller W Jr et al (1962) Cryoglobu­linemia based on interaction between a gamma macroglobulin and 7S gamma globulin. Am J Med 32:142–147PubMedCrossRefGoogle Scholar
  4. 4.
    Meltzer M, Franklin EC (1966) Cryoglobulinemia – a study of twenty-nine patients. I. IgG and IgM cryoglobulins and factors affecting cryoprecipitability. Am J Med 40:828–836PubMedCrossRefGoogle Scholar
  5. 5.
    Meltzer M, Franklin EC, Elias K et al (1966) Cryoglobu­linemia – a clinical and laboratory study. II. Cryoglobulins with rheumatoid factor activity. Am J Med 40:837–856PubMedCrossRefGoogle Scholar
  6. 6.
    Brouet JC, Clauvel JP, Danon F et al (1974) Biological and clinical significance of cryoglobulins. Am J Med 57:775–788PubMedCrossRefGoogle Scholar
  7. 7.
    Wager O, Mustakallio KK, Räsänen JA (1968) Mixed IgA-IgG cryoglobulinemia. Immunological studies and case reports of three patients. Am J Med 44:179–187PubMedCrossRefGoogle Scholar
  8. 8.
    Barnett EV, Bluestone R, Cracchiolo A III et al (1970) Cryoglobulinemia and disease. Ann Intern Med 73:95–107PubMedCrossRefGoogle Scholar
  9. 9.
    Kunkel HG, Agnello V, Joslin FG et al (1973) Cross-idiotypic specificity among monoclonal IgM proteins with anti-globulin activity. J Exp Med 137:331–342PubMedCrossRefGoogle Scholar
  10. 10.
    Gorevic PD, Frangione B (1991) Mixed cryoglobulinemia cross-reactive idiotypes: implications for the relationship of MC to rheumatic and lymphoproliferative diseases. Semin Hematol 28:79–94PubMedGoogle Scholar
  11. 11.
    Dammacco F, Sansonno D, Piccoli C et al (2001) The ­cryoglobulins: an overview. Eur J Clin Invest 31:628–638PubMedCrossRefGoogle Scholar
  12. 12.
    Levo Y, Gorevic PD, Kassab HJ et al (1977) Association between hepatitis B virus and essential mixed cryoglobulinemia. N Engl J Med 297:946–947Google Scholar
  13. 13.
    Galli M, Monti G, Invernizzi F et al (1992) Hepatitis B virus-related markers in secondary and in essential mixed cryoglobulinemias: a multicentric study of 596 cases. The Italian Group for the Study of Cryoglobulinemias (GISC). Ann Ital Med Int 7:209–214PubMedGoogle Scholar
  14. 14.
    Christodoulou DK, Dalekos GN, Merkouropoulos MH et al (2001) Cryoglobulinemia due to chronic viral hepatitis infections is not a major problem in clinical practice. Eur J Intern Med 12:435–441PubMedCrossRefGoogle Scholar
  15. 15.
    Pascual M, Perrin L, Giostra E et al (1990) Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis 162:569–570PubMedCrossRefGoogle Scholar
  16. 16.
    Ferri C, Greco F, Longombardo G et al (1991) Antibodies against hepatitis C virus in mixed cryoglobulinemia patients. Infection 19:417–420PubMedCrossRefGoogle Scholar
  17. 17.
    Dammacco F, Sansonno D (1992) Antibodies to hepatitis C virus in essential mixed cryoglobulinaemia. Clin Exp Immunol 87:352–356PubMedCrossRefGoogle Scholar
  18. 18.
    Misiani R, Bellavita P, Fenili D et al (1992) Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 117:573–577PubMedCrossRefGoogle Scholar
  19. 19.
    Cacoub P, Musset L, Lunel Fabiani F et al (1993) Hepatitis C virus and essential mixed cryoglobulinaemia. Br J Rheumatol 32:689–692PubMedCrossRefGoogle Scholar
  20. 20.
    Dammacco F, Sansonno D, Cornacchiulo V et al (1993) Hepatitis C virus infection and mixed cryoglobulinemia: a striking association. Int J Clin Lab Res 23:45–49PubMedCrossRefGoogle Scholar
  21. 21.
    Marcellin P, Descamps V, Martinot-Peignoux M et al (1993) Cryoglobulinemia with vasculitis associated with hepatitis C virus infection. Gastroenterology 104:272–277PubMedGoogle Scholar
  22. 22.
    Agnello V, Chung RT, Kaplan LM (1992) A role for ­hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 327:1490–1495PubMedCrossRefGoogle Scholar
  23. 23.
    Levey JM, Bjornsson B, Banner B et al (1994) Mixed ­cryoglobulinemia in chronic hepatitis C infection. A clinicopathologic analysis of 10 cases and review of recent literature. Medicine (Baltimore) 73:53–67Google Scholar
  24. 24.
    Casato M, Lilli D, Donato G et al (2003) Occult hepatitis C virus infection in type II mixed cryoglobulinaemia. J Viral Hepat 10:455–459PubMedCrossRefGoogle Scholar
  25. 25.
    Sansonno D, Lauletta G, De Re V et al (2004) Intrahepatic B cell clonal expansions and extrahepatic manifestations of chronic HCV infection. Eur J Immunol 34:126–136PubMedCrossRefGoogle Scholar
  26. 26.
    Vallat L, Benhamou Y, Gutierrez M et al (2004) Clonal B cell populations in the blood and liver of patients with chronic hepatitis C virus infection. Arthritis Rheum 50:3668–3678PubMedCrossRefGoogle Scholar
  27. 27.
    Sansonno D, Dammacco F (2005) Hepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations. Lancet Infect Dis 5:227–236PubMedCrossRefGoogle Scholar
  28. 28.
    Sitia G, Isogawa M, Iannacone M et al (2004) MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs. J Clin Invest 113:1158–1167PubMedGoogle Scholar
  29. 29.
    Sansonno D, Tucci FA, Troiani L et al (2008) Increased serum levels of the chemokine CXCL13 and up-regulation of its gene expression are distinctive features of HCV-related cryoglobulinemia and correlate with active cutaneous vasculitis. Blood 112:1620–1627PubMedCrossRefGoogle Scholar
  30. 30.
    Dustin LB, Rice CM (2007) Flying under the radar: the immunobiology of hepatitis C. Annu Rev Immunol 25:71–99PubMedCrossRefGoogle Scholar
  31. 31.
    Wieland SF, Chisari FV (2005) Stealth and cunning: hepatitis B and hepatitis C viruses. J Virol 79:9369–9380PubMedCrossRefGoogle Scholar
  32. 32.
    Klenerman P, Zinkernagel RM (1998) Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes. Nature 394:482–485PubMedCrossRefGoogle Scholar
  33. 33.
    Ferri C, La Civita L, Longombardo G et al (1998) Mixed cryoglobulinaemia: a cross-road between autoimmune and lymphoproliferative disorders. Lupus 7:275–279PubMedCrossRefGoogle Scholar
  34. 34.
    Dammacco F, Sansonno D, Piccoli C et al (2000) The lymphoid system in hepatitis C virus infection: autoimmunity, mixed cryoglobulinemia, and overt B-cell malignancy. Semin Liver Dis 20:143–157PubMedCrossRefGoogle Scholar
  35. 35.
    Ferri C, Caracciolo F, Zignego AL et al (1994) Hepatitis C virus infection in patients with non-Hodgkin’s lymphoma. Br J Haematol 88(2):392–394PubMedCrossRefGoogle Scholar
  36. 36.
    Pozzato G, Mazzaro C, Crovatto M et al (1994) Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia. Blood 84(9):3047–3053PubMedGoogle Scholar
  37. 37.
    Monti G, Pioltelli P, Saccardo F (2005) Incidence and characteristics of non-Hodgkin lymphomas in a multicenter case file of patients with hepatitis C virus-related symptomatic mixed cryoglobulinemias. Arch Intern Med 165:101–105PubMedCrossRefGoogle Scholar
  38. 38.
    Marcucci F, Mele A (2011) Hepatitis viruses and non-Hodgkin lymphoma: epidemiology, mechanisms of tumorigenesis and therapeutic opportunities. Blood 117(6):1792–1798PubMedCrossRefGoogle Scholar
  39. 39.
    Libra M, Polesel J, Russo AE et al (2010) Extrahepatic disorders of HCV infection: a distinct entity of B-cell neoplasia? Int J Oncol 36:1331–1340PubMedCrossRefGoogle Scholar
  40. 40.
    Omland LH, Farkas DK, Jepsen P et al (2010) Hepatitis C virus infection and risk of cancer: a population-based cohort study. Clin Epidemiol 2:179–186PubMedGoogle Scholar
  41. 41.
    Hermine O, Lefrere F, Bronowicki JP et al (2002) Regression of splenic lymphoma with villous lymphocytes after ­treatment of hepatitis C virus infection. N Engl J Med 347:89–94PubMedCrossRefGoogle Scholar
  42. 42.
    Gisbert JP, García-Buey L, Pajares JM et al (2005) Systematic review: regression of lymphoproliferative disorders after treatment for hepatitis C infection. Aliment Pharmacol Ther 21:653–662PubMedCrossRefGoogle Scholar
  43. 43.
    Kawamura Y, Ikeda K, Arase Y et al (2007) Viral elimination reduces incidence of malignant lymphoma in patients with hepatitis C. Am J Med 120:1034–1041PubMedCrossRefGoogle Scholar
  44. 44.
    Knight GB, Gao L, Gragnani L (2010) Detection of WA B cells in hepatitis C virus infection: a potential prognostic marker for cryoglobulinemic vasculitis and B cell malignancies. Arthritis Rheum 62:2152–2159PubMedGoogle Scholar
  45. 45.
    Bonomo L, Casato M, Afeltra A et al (1987) Treatment of idiopathic mixed cryoglobulinemia with alpha interferon. Am J Med 83:726–730PubMedCrossRefGoogle Scholar
  46. 46.
    Saadoun D, Delluc A, Piette JC et al (2008) Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis. Curr Opin Rheumatol 20:23–28PubMedGoogle Scholar
  47. 47.
    Sansonno D, De Re V, Lauletta G et al (2003) Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-CD20. Blood 101:3818–3826PubMedCrossRefGoogle Scholar
  48. 48.
    Zaja F, De Vita S, Mazzaro C et al (2003) Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 101:3827–3834PubMedCrossRefGoogle Scholar
  49. 49.
    Cacoub P, Saadoun D, Limal N et al (2005) PEGylated ­interferon alfa-2b and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis. Arthritis Rheum 52:911–915PubMedCrossRefGoogle Scholar
  50. 50.
    Saadoun D, Resche Rigon M, Sene D et al (2010) Rituximab plus Peg-interferon-alpha/ribavirin compared with Peg-interferon-alpha/ribavirin in hepatitis C-related mixed cryoglobulinemia. Blood 116:326–334PubMedCrossRefGoogle Scholar
  51. 51.
    Dammacco F, Tucci FA, Lauletta G et al (2010) Pegylated interferon-alpha, ribavirin, and rituximab combined therapy of hepatitis C virus-related mixed cryoglobulinemia: a long-term study. Blood 116:343–353PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2012

Authors and Affiliations

  1. 1.Department of Internal Medicine and Clinical OncologyUniversity of Bari Medical SchoolBariItaly
  2. 2.Liver Unit, Department of Biomedical Sciences and Clinical OncologyUniversity of Bari Medical SchoolBariItaly

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