Skip to main content

Advertisement

SpringerLink
Log in

Rituximab as a Therapeutic Tool in Severe Mixed Cryoglobulinemia

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

Type II mixed cryoglobulinemia (MC) is a systemic vasculitis, associated in most cases with hepatitis C virus (HCV) infection, sustained by proliferation of oligoclonal cells. Systemic B cell depletion and clinical remission can be achieved in non-Hodgkin lymphoma by human/mouse chimeric monoclonal antibody that specifically reacts with the CD20 antigen (rituximab). Similar effects could be expected in type II MC. Twelve patients, mean age 61.9 years (range 37–76), 11 with HCV infection genotype 2a2c (4 cases) or 1b (6 cases) and 3 (1 case) and symptomatic type II MC with systemic manifestations, including renal involvement, marrow clonal restriction, large necrotizing ulcers, and polyneuropathy, were considered eligible for rituximab therapy because of resistance or intolerance to conventional therapy or important bone marrow infiltration. Rituximab was administered intravenously at a dose of 375 mg/m2 on days 1, 8, 15, and 22. Two more doses were administered 1 and 2 months later. No other immunosuppressive drugs were added. Response was evaluated by assessing the changes in clinical signs, symptoms, and laboratory parameters. Levels of proteinuria, hematuria, erythrocyte sedimentation rate, cryocrit, rheumatoid factor, and IgM decreased while C4 values increased and HCV viral load remained stable during short- and medium-term observation. Bone marrow abnormalities were found to reverse to normal. Constitutional symptoms disappeared or ameliorated. No acute or delayed side effects were seen. Based on this experience and a number of reports published in the last 5 years, Rituximab appears to be a safe and effective therapeutic option in symptomatic patients with HCV-associated MC with signs of systemic vasculitis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M (1974) Biological and clinical significance of cryoglobulins. A report of 86 cases. Am J Med 57:775–778

    Article  PubMed  CAS  Google Scholar 

  2. Meltzer M, Franklin EC, Elias K et al (1966) Cryoglobulinemia, a clinical and laboratory study. II. Cryoglobulins with rheumatoid factor activity. Am J Med 40:837–856

    Article  PubMed  CAS  Google Scholar 

  3. Gorevic PD, Kassab HJ, Levo Y et al (1980) Mixed cryoglobulinemia: clinical aspects and long-term follow-up of 40 patients. Am J Med 69:287–308

    Article  PubMed  CAS  Google Scholar 

  4. D’Amico G, Colasanti G, Ferrario F, Sinico RA (1989) Renal involvement in essential mixed cryoglobulinemia. Kidney Int 35:1004–1014

    Article  PubMed  CAS  Google Scholar 

  5. Pascual M, Perrin L, Giostra E, Schifferli JA (1990) Hepatitis C virus in patients with cryoglobulinemia type II. Infectious Dis 162:569–575

    CAS  Google Scholar 

  6. Durand JM, Lefevre P, Harle JR et al (1991) Cutaneous vasculitis and cryoglobulinemia type II associated with hepatitis C virus infection. Lancet 337:499–500

    Article  PubMed  CAS  Google Scholar 

  7. Casato M, Taliani G, Pucillo L et al (1991) Cryoglobulinemia and hepatitis C virus. Lancet 337:449–453

    Article  Google Scholar 

  8. Misiani R, Bellavita P, Fenili D et al (1992) Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 117:573–577

    PubMed  CAS  Google Scholar 

  9. Ferri C, Longombardo G, La Civita L et al (1992) Hepatitis C virus, autoimmune liver disease and cryoglobulinemic hepatitis. J Hepatol 16:242–243

    Article  PubMed  CAS  Google Scholar 

  10. Agnello V, Chung RT, Kaplan LM (1992) A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 327:1490–1495

    Article  PubMed  CAS  Google Scholar 

  11. Ferri C, Monti M, La Civita L et al (1993) Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia. Blood 82:3701–3704

    PubMed  CAS  Google Scholar 

  12. Invernizzi F, Pioltelli P, Cattaneo R et al (1979) A long-term follow-up study in essential cryoglobulinemia. Acta Haematol 61:93–99

    PubMed  CAS  Google Scholar 

  13. Tarantino A, De Vecchi A, Montagnino G et al (1981) Renal disease in essential mixed cryoglobulinemia. Long term follow-up of 44 patients. Q J Med 50:1–30

    PubMed  CAS  Google Scholar 

  14. Monti G, Galli M, Invernizzi F et al (1995) Cryoglobulinemias: a multi-centre study of the early clinical and laboratory manifestations of primary and secondary disease. GISC. Italian Group for the Study of Cryoglobulinemias. QJM 88:115–126

    PubMed  CAS  Google Scholar 

  15. Rieu V, Cohen P, Andrè MH et al (2002) Characteristics and outcome of 49 patients. Rheumatology 41:290–300

    Article  PubMed  CAS  Google Scholar 

  16. Tarantino A, Campise M, Banfi G et al (1995) Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int 47:618–623

    Article  PubMed  CAS  Google Scholar 

  17. Roccatello D, Fornasieri A, Giachino O et al (2007) Multicenter study on HCV-related cryoglobulinemic glomerulonephritis. Am J Kidney Dis 49:69–82

    Article  PubMed  CAS  Google Scholar 

  18. Roccatello D, Isidoro C, Mazzucco G et al (1993) Role of monocytes in cryoglobulinemia-associated nephritis. Kidney Int 43:1150–1155

    Article  PubMed  CAS  Google Scholar 

  19. Ferri C, Mascia MT (2006) Cryoglobulinemic vasculitis. Curr Opin Rheumatol 18:54–63

    Article  PubMed  Google Scholar 

  20. Fornasieri A, Li M, Armelloni S et al (1993) Glomerulonephritis induced by human IgMk–IgG cryoglobulins in mice. Lab Invest 69:531–540

    PubMed  CAS  Google Scholar 

  21. Roccatello D, Morsica G, Picciotto G et al (1997) Impaired hepatosplenic elimination of circulating cryoglobulins in patients with essential mixed cryoglobulinemia and hepatitis C virus (HCV) infection. Clin Exp Immunol 110:9–14

    Article  PubMed  CAS  Google Scholar 

  22. Pileri P, Uematsu Y, Campagnoli S et al (1998) Binding of hepatitis C virus to CD81. Science 282:938–941

    Article  PubMed  CAS  Google Scholar 

  23. Roccatello D, Giachino O, Fornasieri A (2000) Forum multidisciplinare su “la sindrome HCV”. G Ital Nefrol 6:654–665

    Google Scholar 

  24. Zignego AL, Giannelli F, Marrocchi ME et al (2000) T [14 18] translocation in chronic hepatitis C virus infection. Hepatology 31:474–479

    Article  PubMed  CAS  Google Scholar 

  25. Maloney DG, Grillo-Lopez AJ, White CA et al (1997) IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 90:2188–2195

    PubMed  CAS  Google Scholar 

  26. Shan D, Ledbetter JA, Press OW (1998) Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies. Blood 91:1644–1652

    PubMed  CAS  Google Scholar 

  27. Byrd JC, White CA, Link B et al (1999) Rituximab therapy in Waldenstrom’s macroglobulinemia: preliminary evidence of clinical activity. Ann Oncol 10:1525–1527

    Article  PubMed  CAS  Google Scholar 

  28. Levine TD, Pestronk A (1999) IgM antibody-related polyneuropathies: B-cell depletion chemotherapy using Rituximab. Neurology 52:1701–1704

    PubMed  CAS  Google Scholar 

  29. Saleh MN, Gutheil J, Moore M et al (2000) A pilot study of the anti-CD20 monoclonal antibody rituximab in patients with refractory immune thrombocytopenia. Semin Oncol 27:99–103

    PubMed  CAS  Google Scholar 

  30. Zecca M, De Stefano P, Nobili B, Locatelli F (2001) Anti-CD20 monoclonal antibody for the treatment of severe, immune-mediated, pure red cell aplasia and hemolytic anemia. Blood 97:3995–3997

    Article  PubMed  CAS  Google Scholar 

  31. Zaja F, De Vita S, Mazzaro C et al (2003) Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 101:3827–3834

    Article  PubMed  CAS  Google Scholar 

  32. Zaja F, Russo D, Fuga G et al (1999) Rituximab for the treatment of type II mixed cryoglobulinemia. Haematologica 84:1157–1158

    PubMed  CAS  Google Scholar 

  33. Della Rossa A, Tavoni A, Baldini C, Bombardieri S (2002) Treatment of chronic hepatitis C infection with cryoglobulinemia. Curr Opin Rheum 13:231–237

    Article  Google Scholar 

  34. Misiani R, Bellavita P, Fenili D et al (1994) Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 330:751–756

    Article  PubMed  CAS  Google Scholar 

  35. Johnson RJ, Gretch DR, Couser WG et al (1994) Hepatitis C virus-associated glomerulonephritis. Effect of alpha-interferon therapy. Kidney Int 46:1700–1704

    Article  PubMed  CAS  Google Scholar 

  36. Rossi P, Bertani T, Baio P et al (2003) Hepatitis C virus-related cryoglobulinemic glomerulonephritis: long-term remission after antiviral therapy. Kidney Int 63:2236–2241

    Article  PubMed  CAS  Google Scholar 

  37. Manns MP, McHutchison JG, Gordon SC et al (2001) Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358:958–965

    Article  PubMed  CAS  Google Scholar 

  38. Lindsay KL, Trepo C, Heintges T et al (2001) A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology 34:395–403

    Article  PubMed  CAS  Google Scholar 

  39. Selby P, Kohn J, Raymond J, Judson I, McElwain T (1985) Nephrotic syndrome during treatment with interferon. Br Med J 290:1180

    Article  CAS  Google Scholar 

  40. Janessen H, Brouwer J, Van der Mast RC, Schalm S (1994) Suicide associated with alpha-interferon therapy for chronic viral hepatitis. J Hepatol 21:241–243

    Article  Google Scholar 

  41. Ferri C, Pileri S, Zignego AL (2000) Hepatitis C virus, B-cell disorders, and non-Hodgkin lymphoma. In: Goedert JJ (ed) Infectious cause of cancer. Target for intervention. Humana, Totowa, pp 349–368

    Chapter  Google Scholar 

  42. Roccatello D, Mazzucco G, Coppo R et al (1991) Immune material processing by phagocyte cell system in cryoglobulinemia. Clin Nephrol 36:114–126

    PubMed  CAS  Google Scholar 

  43. Margin S, Craxi A, Fabiano C et al (1994) Hepatitis C viraemia in chronic liver disease: relationship to interferon alpha or corticosteroid treatment. Hepatology 19:273–279

    Google Scholar 

  44. Roccatello D, Baldovino S, Rossi D et al (2004) Long term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinemic glomerulonephritis. Nephrol Dial Transplant 19:3054–3061

    Article  PubMed  CAS  Google Scholar 

  45. Looney RJ (2002) Treating human autoimmune disease by depleting B cells. Ann Rheum Dis 61:863–866

    Article  PubMed  CAS  Google Scholar 

  46. Arzoo K, Sadeghi S, Liebman HA (2002) Treatment of refractory antibody mediated autoimmune disorders with an anti-CD20 monoclonal antibody Rituximab. Ann Rheum Dis 61:922–924

    Article  PubMed  CAS  Google Scholar 

  47. Treon SP, Anderson KC (2000) The use of rituximab in the treatment of malignant and non-malignant plasma cell disorders. Semin Oncol 27:79–85

    PubMed  CAS  Google Scholar 

  48. Clynes RA, Towers TL, Presta LG, Ravetch JV (2000) Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med 6:443–446

    Article  PubMed  CAS  Google Scholar 

  49. Sansonno D, De Re V, Lauretta G et al (2003) Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alfa with an anti-CD20. Blood 101:3818–3826

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of Interest

There are no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Centro Multidisciplinare di Ricerche di Immunopatologia e Documentazione su Malattie Rare, Struttura Complessa a Direzione Universitaria di Immunologia Clinica (CMID), Ospedale S.G. Bosco, L.go Donatore del Sangue 3, 10154, Torino, Italy

    Dario Roccatello, Daniela Rossi, Osvaldo Giachino, Carla Naretto, Roberto Cavallo & Mirella Alpa

  2. Dipartimento di Medicina e Oncologia Sperimentale, Sezione di Patologia Generale, Università di Torino, Torino, Italy

    Simone Baldovino, Morteza Mansouri, Debora Di Simone, Simona Francica, Franca Napoli & Luigi M. Sena

Authors
  1. Dario Roccatello
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simone Baldovino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniela Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Osvaldo Giachino
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Morteza Mansouri
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carla Naretto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Debora Di Simone
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Simona Francica
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Roberto Cavallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mirella Alpa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Franca Napoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Luigi M. Sena
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dario Roccatello.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roccatello, D., Baldovino, S., Rossi, D. et al. Rituximab as a Therapeutic Tool in Severe Mixed Cryoglobulinemia. Clinic Rev Allerg Immunol 34, 111–117 (2008). https://doi.org/10.1007/s12016-007-8019-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-007-8019-0

Keywords

Search

Navigation