Novel Therapeutic Approaches to Cryoglobulinemia: Imatinib, Infliximab, Bortezomib, and Beyond



Cryoglobulinemia is a rare disorder characterized by the development of leukocytoclastic necrotizing vasculitis. Currently, the conventional treatment of cryoglobulinemia in the absence of viral infection involves corticosteroids, immunosuppressive drugs, and plasma exchange. Patients with relapsed or refractory disease require additional therapies, but no established guidelines regarding the treatment of these patients are available. The recent molecular revolution has resulted in an armamentarium of targeted biologic agents, and several of these novel drugs have been shown to be active in patients with refractory cryoglobulinemia. This chapter reviews the clinical results and rationale of several emerging agents for cryoglobulinemia, including TNF inhibitors, the immunomodulator drugs thalidomide and lenalidomide, and the proteasome inhibitor bortezomib.


Multiple Myeloma Chronic Lymphocytic Leukemia Plasma Exchange Hairy Cell Leukemia Mixed Cryoglobulinemia 
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  1. 1.
    Dammacco F, Sansonno D, Piccoli C et al (2001) The cryoglobulins: an overview. Eur J Clin Invest 31:628–638PubMedCrossRefGoogle Scholar
  2. 2.
    Dammacco F, Sansonno D (1997) Mixed cryoglobulinemia as a model of systemic vasculitis. Clin Rev Allergy Immunol 15:97–119PubMedCrossRefGoogle Scholar
  3. 3.
    Agnello V (1997) The etiology and pathophysiology of mixed cryoglobulinemia secondary to hepatitis C virus infection. Springer Semin Immunopathol 19:111–129PubMedCrossRefGoogle Scholar
  4. 4.
    Brouet JC, Clauvel JP, Danon F et al (1974) Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med 57:775–788PubMedCrossRefGoogle Scholar
  5. 5.
    Golde D, Epstein W (1968) Mixed cryoglobulins and glomerulonephritis. Ann Intern Med 69:1221–1227PubMedCrossRefGoogle Scholar
  6. 6.
    Ristow SC, Griner PF, Abraham GN et al (1976) Reversal of systemic manifestations of cryoglobulinemia. Treatment with melphalan and prednisone. Arch Intern Med 136:467–470PubMedCrossRefGoogle Scholar
  7. 7.
    Barnett EV, Bluestone R, Cracchiolo A 3rd et al (1970) Cryoglobulinemia and disease. Ann Intern Med 73:95–107PubMedCrossRefGoogle Scholar
  8. 8.
    Mathison DA, Condemi JJ, Leddy JP et al (1971) Purpura, arthralgia, and IgM-IgM cryoglobulinemia with rheumatoid factor activity. Response to cyclophosphamide and splenectomy. Ann Intern Med 74:383–390PubMedCrossRefGoogle Scholar
  9. 9.
    Frankel AH, Singer DR, Winearls CG et al (1992) Type II essential mixed cryoglobulinaemia: presentation, treatment and outcome in 13 patients. Q J Med 82:101–124PubMedGoogle Scholar
  10. 10.
    Ramos-Casals M, Brito-Zeron P, Munoz S et al (2008) A systematic review of the off-label use of biological therapies in systemic autoimmune diseases. Medicine (Baltimore) 87:345–364CrossRefGoogle Scholar
  11. 11.
    Lamprecht P, Lerin-Lozano C, Merz H et al (2003) Rituximab induces remission in refractory HCV associated cryoglobulinaemic vasculitis. Ann Rheum Dis 62:1230–1233PubMedCrossRefGoogle Scholar
  12. 12.
    Cacoub P, Delluc A, Saadoun D et al (2008) Anti-CD20 monoclonal antibody (rituximab) treatment for cryoglobulinemic vasculitis: where do we stand? Ann Rheum Dis 67:283–287PubMedCrossRefGoogle Scholar
  13. 13.
    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
  14. 14.
    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
  15. 15.
    Valesini G, Iannuccelli C, Marocchi E et al (2007) Biological and clinical effects of anti-TNFalpha treatment. Autoimmun Rev 7:35–41PubMedCrossRefGoogle Scholar
  16. 16.
    Kaplanski G, Marin V, Maisonobe T et al (2002) Increased soluble p55 and p75 tumour necrosis factor-alpha receptors in patients with hepatitis C-associated mixed cryoglobulinaemia. Clin Exp Immunol 127:123–130PubMedCrossRefGoogle Scholar
  17. 17.
    Booth A, Harper L, Hammad T et al (2004) Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol 15:717–721PubMedCrossRefGoogle Scholar
  18. 18.
    Bartolucci P, Ramanoelina J, Cohen P et al (2002) Efficacy of the anti-TNF-alpha antibody infliximab against refractory systemic vasculitides: an open pilot study on 10 patients. Rheumatology (Oxford) 41:1126–1132CrossRefGoogle Scholar
  19. 19.
    Josselin L, Mahr A, Cohen P et al (2008) Infliximab efficacy and safety against refractory systemic necrotising vasculitides: long-term follow-up of 15 patients. Ann Rheum Dis 67:1343–1346PubMedCrossRefGoogle Scholar
  20. 20.
    Lamprecht P, Voswinkel J, Lilienthal T et al (2002) Effectiveness of TNF-alpha blockade with infliximab in refractory Wegener’s granulomatosis. Rheumatology (Oxford) 41:1303–1307CrossRefGoogle Scholar
  21. 21.
    Mukhtyar C, Hellmich B, Jayne D et al (2006) Remission in antineutrophil cytoplasmic antibody-associated systemic vasculitis. Clin Exp Rheumatol 24:S-93–S-98Google Scholar
  22. 22.
    Chandesris MO, Gayet S, Schleinitz N et al (2004) Infliximab in the treatment of refractory vasculitis secondary to hepatitis C-associated mixed cryoglobulinaemia. Rheumatology (Oxford) 43:532–533CrossRefGoogle Scholar
  23. 23.
    Koukoulaki M, Abeygunasekara SC, Smith KG et al (2005) Remission of refractory hepatitis C-negative cryoglobulinaemic vasculitis after rituximab and infliximab. Nephrol Dial Transplant 20:213–216PubMedCrossRefGoogle Scholar
  24. 24.
    Bratcher JM, Korelitz BI (2006) Toxicity of infliximab in the course of treatment of Crohn’s disease. Expert Opin Drug Saf 5:9–16PubMedCrossRefGoogle Scholar
  25. 25.
    Sieper J, Van Den Brande J (2005) Diverse effects of infliximab and etanercept on T lymphocytes. Semin Arthritis Rheum 34:23–27PubMedCrossRefGoogle Scholar
  26. 26.
    Sandborn WJ, Hanauer SB, Katz S et al (2001) Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 121:1088–1094PubMedCrossRefGoogle Scholar
  27. 27.
    Marotte H, Fontanges E, Bailly F et al (2007) Etanercept treatment for three months is safe in patients with rheumatological manifestations associated with hepatitis C virus. Rheumatology (Oxford) 46:97–99CrossRefGoogle Scholar
  28. 28.
    Vauloup C, Krzysiek R, Greangeot-Keros L et al (2006) Effects of tumor necrosis factor antagonist treatment on hepatitis C-related immunological abnormalities. Eur Cytokine Netw 17:290–293PubMedGoogle Scholar
  29. 29.
    Hunter T (2007) Treatment for chronic myelogenous leukemia: the long road to imatinib. J Clin Invest 117:2036–2043PubMedCrossRefGoogle Scholar
  30. 30.
    Iyoda M, Hudkins KL, Becker-Herman S et al (2009) Imatinib suppresses cryoglobulinemia and secondary membranoproliferative glomerulonephritis. J Am Soc Nephrol 20:68–77PubMedCrossRefGoogle Scholar
  31. 31.
    Lam QL, Lo CK, Zheng BJ et al (2007) Impaired V(D)J recombination and increased apoptosis among B cell precursors in the bone marrow of c-Abl-deficient mice. Int Immunol 19:267–276PubMedCrossRefGoogle Scholar
  32. 32.
    Rolink A, Streb M, Nishikawa S et al (1991) The c-kit-encoded tyrosine kinase regulates the proliferation of early pre-B cells. Eur J Immunol 21:2609–2612PubMedCrossRefGoogle Scholar
  33. 33.
    Nehme-Schuster H, Korganow AS, Pasquali JL et al (2005) Rituximab inefficiency during type I cryoglobulinaemia. Rheumatology (Oxford) 44:410–411CrossRefGoogle Scholar
  34. 34.
    Gertz MA, Anagnostopoulos A, Anderson K et al (2003) Treatment recommendations in Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. Semin Oncol 30:121–126PubMedCrossRefGoogle Scholar
  35. 35.
    Kapoor P, Greipp PT, Morice WG et al (2008) Anti-CD20 monoclonal antibody therapy in multiple myeloma. Br J Haematol 141:135–148PubMedCrossRefGoogle Scholar
  36. 36.
    Moreau P, Voillat L, Benboukher L et al (2007) Rituximab in CD20 positive multiple myeloma. Leukemia 21:835–836PubMedGoogle Scholar
  37. 37.
    Chu D, Stevens M, Gladstone DE (2007) Severe, refractory, non-malignant type I cryoglobulinemia treated with alemtuzumab. Rheumatol Int 27:1173–1175PubMedCrossRefGoogle Scholar
  38. 38.
    Gribben JG, Hallek M (2009) Rediscovering alemtuzumab: current and emerging therapeutic roles. Br J Haematol 144:818–831PubMedCrossRefGoogle Scholar
  39. 39.
    Knight R (2005) IMiDs: a novel class of immunomodulators. Semin Oncol 32:S24–S30PubMedCrossRefGoogle Scholar
  40. 40.
    Palumbo A, Facon T, Sonneveld P et al (2008) Thalidomide for treatment of multiple myeloma: 10 years later. Blood 111:3968–3977PubMedCrossRefGoogle Scholar
  41. 41.
    Paravar T, Lee DJ (2008) Thalidomide: mechanisms of action. Int Rev Immunol 27:111–135PubMedCrossRefGoogle Scholar
  42. 42.
    Sampson A, Callen JP (2006) The cutting edge: thalidomide for type 1 cryoglobulinemic vasculopathy. Arch Dermatol 142:972–974PubMedCrossRefGoogle Scholar
  43. 43.
    Cem Ar M, Soysal T, Hatemi G et al (2005) Successful management of cryoglobulinemia-induced leukocytoclastic vasculitis with thalidomide in a patient with multiple myeloma. Ann Hematol 84:609–613PubMedCrossRefGoogle Scholar
  44. 44.
    Witzens M, Moehler T, Neben K et al (2004) Development of leukocytoclastic vasculitis in a patient with multiple myeloma during treatment with thalidomide. Ann Hematol 83:467–470PubMedCrossRefGoogle Scholar
  45. 45.
    Lin RJ, Curran JJ, Zimmerman TM et al (2010) Lenalidomide for the treatment of cryoglobulinemia and undifferentiated spondyloarthropathy in a patient with multiple myeloma. J Clin Rheumatol 16:90–91PubMedCrossRefGoogle Scholar
  46. 46.
    Talamo G, Claxton D, Tricot G et al (2008) Response to bortezomib in refractory type I cryoglobulinemia. Am J Hematol 83:883–884PubMedCrossRefGoogle Scholar
  47. 47.
    Cavo M (2006) Proteasome inhibitor bortezomib for the treatment of multiple myeloma. Leukemia 20:1341–1352PubMedCrossRefGoogle Scholar
  48. 48.
    Chad D, Pariser K, Bradley WG et al (1982) The pathogenesis of cryoglobulinemic neuropathy. Neurology 32:725–729PubMedCrossRefGoogle Scholar
  49. 49.
    Zaltron S, Puoti M, Liberini P et al (1998) High prevalence of peripheral neuropathy in hepatitis C virus infected patients with symptomatic and asymptomatic cryoglobulinaemia. Ital J Gastroenterol Hepatol 30:391–395PubMedGoogle Scholar
  50. 50.
    Roccatello D, Fornasieri A, Giachino O et al (2007) Multicenter study on hepatitis C virus-related cryoglobulinemic glomerulonephritis. Am J Kidney Dis 49:69–82PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2012

Authors and Affiliations

  1. 1.Division of Hematology-OncologyPenn State Hershey Cancer InstituteHersheyUSA
  2. 2.Division of Hematology, Blood/Marrow Transplant and Myeloma ProgramUniversity of UtahSalt Lake CityUSA

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