The American Journal of Medicine
Volume 123, Issue 5 , Pages 400-408 , May 2010

Management of Hepatitis C Virus-related Mixed Cryoglobulinemia

  • Francesco Iannuzzella, MD
    • ,
  • Augusto Vaglio, MD
    • ,
  • Giovanni Garini, MD

      Affiliations

    • Corresponding Author InformationRequests for reprints should be addressed to Giovanni Garini, MD, Department of Internal Medicine, Nephrology and Health Sciences, Ospedale Maggiore, Via A. Gramsci 14, Parma 43100, Italy

References 

  1. Wintrobe MM, Buell MV. Hypoproteinemia associated with multiple myeloma. Bull Johns Hopkins Hosp. 1933;52:156–165
  2. Brouet JC, Clauvel JP, Danon F, et al. Biologic and clinical significance of cryoglobulins (A report of 86 cases). Am J Med. 1974;57:775–788
  3. Lospalluto J, Dorward B, Miller W, Ziff M. Cryoglobulinemia based on interaction between a gamma macroglobulin and 7S gamma globulin. Am J Med. 1962;32:142–145
  4. Ferri C, Zignego AL, Pileri SA. Cryoglobulins. J Clin Pathol. 2002;55:4–13
  5. Lamprecht P, Gause A, Gross WL. Cryoglobulinemic vasculitis. Arthritis Rheum. 1999;42:2507–2516
  6. Pascual M, Perrin L, Giostra E, Schifferli J. Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis. 1990;162:569–570
  7. Casato M, Pucillo LP, Lagana B, et al. Cryoglobulinemia and hepatitis C virus. Lancet. 1991;337:1047–1048
  8. Disdier P, Harle JR, Weiller PJ. Cryoglobulinemia and hepatitis C virus infection. Lancet. 1991;338:1151–1152
  9. Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med. 1992;327:1490–1495
  10. Monti G, Galli M, Invernizzi F, et al. Cryoglobulinaemias: a multi-centre study of the early clinical and laboratory manifestations of primary and secondary disease (GISC. Italian Group for the Study of Cryoglobulinaemias). QJM. 1995;88:115–126
  11. Cacoub P, Musset L, Lunel-Fabiani F, et al. Hepatitis C virus and essential mixed cryoglobulinemia. Br J Rheumatol. 1993;32:685–692
  12. Mayo MJ. Extrahepatic manifestations of hepatitis C infection. Am J Med Sci. 2003;325:135–148
  13. Gorevic PD, Frangione B. Mixed cryoglobulinemia crossreactive idiotypes: Implications for the relationship of MC to rheumatic and lymphoproliferative diseases. Semin Hematol. 1991;28:79–94
  14. Agnello V. The etiology and pathophysiology of mixed cryoglobulinemia secondary to hepatitis C virus infection. Springer Semin Immunopathol. 1997;19:111–129
  15. Pileri P, Uematsu Y, Campagnoli S, et al. Binding of hepatitis C virus to CD81. Science. 1998;282:938–941
  16. Monti G, Pioltelli P, Saccardo F, et al. 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. 2005;165:101–105
  17. Kayali Z, Buckwold VE, Zimmerman B, Scmidt WN. Hepatitis C, cryoglobulinemia, and cirrhosis: a meta-analysis. Hepatology. 2002;36:978–985
  18. Agnello V, De Rosa FG. Extrahepatic disease manifestations of HCV infection: some current issues. J Hepatol. 2004;40:341–352
  19. Sène D, Limal N, Cacoub P. Hepatitis C virus-associated extrahepatic manifestations: a review. Metab Brain Dis. 2004;19:357–381
  20. Gorevich PD, Kassab HJ, Levo Y, et al. Mixed cryoglobulinemia: clinical aspects and long-term follow-up of 40 patients. Am J Med. 1980;69:287–308
  21. Meltzer M, Franklin EC. Cryoglobulinemia: a study of 29 patients. I (IgG and IgM cryoglobulins and factors affecting cryoprecipitability). Am J Med. 1966;40:828–836
  22. Ferri C, Sebastiani M, Giuggioli D, et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum. 2004;33:355–374
  23. Agnello V, Abel G. Localization of hepatitis C virus in cutaneous vasculitic lesions in patients with type II cryoglobulinemia. Arthritis Rheum. 1997;40:2007–2015
  24. Johnson RJ, Willson R, Yamabe H, et al. Renal manifestations of hepatitis C virus infection. Kidney Int. 1994;46:1255–1263
  25. Tarantino A, Campise M, Banfi G, et al. Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int. 1995;47:618–623
  26. D'Amico G. Renal involvement in hepatitis C infection: cryoglobulinemic glomerulonephritis. Kidney Int. 1998;54:650–671
  27. 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
  28. Smith KD, Alpers CE. Pathogenic mechanism in membranoproliferative glomerulonephritis. Curr Opin Nephrol Hypertens. 2005;14:396–403
  29. Zaltron S, Puoti M, Liberini P, et al. High prevalence of peripheral neuropathy in hepatitis C virus infected patients with symptomatic and asymptomatic cryoglobulinemia. Ital J Gastroenterol Hepatol. 1998;30:391–395
  30. Apartis E, Leger J-M, Musset L, et al. Peripheral neuropathy associated with essential mixed cryoglobulinaemia: a role for hepatitis C virus infection?. J Neurol Neurosurg Psychiatry. 1996;60:661–666
  31. Boukhris S, Magy L, Senga-mokono U, Loustaud-ratti V, Vallat JM. Polyneuropathy with demyelinating features in mixed cryoglobulinemia with hepatitis C virus infection. Eur J Neurol. 2006;13:937–941
  32. Alpa M, Ferrero B, Cavallo R, et al. Anti-neuronal antibodies in patients with HCV-related mixed cryoglobulinemia. Autoimmun Rev. 2008;8:56–58
  33. Lee YH, Ji JD, Yeon JE, et al. Cryoglobulinemia and rheumatic manifestations in patients with hepatitis C virus infection. Ann Rheum Dis. 1998;57:728–731
  34. Sene D, Ghillani-Dalbin P, Limal N, et al. Anti-cyclic citrullinated peptide antibodies in hepatitis C virus associated rheumatological manifestations and Sjögren's syndrome. Ann Rheum Dis. 2006;65:394–397
  35. Matsumori A, Ohashi N, Hasegawa K, et al. Hepatitis C virus infection and heart diseases: a multicenter study in Japan. Jpn Circ J. 1998;62:389–391
  36. Manganelli P, Salaffi F, Subiaco S, et al. Bronchoalveolar lavage in mixed cryoglobulinaemia associated with hepatitis C virus. Br J Rheumatol. 1996;35:978–982
  37. Ferri C, La Civita L, Fazzi P, et al. Interstitial lung fibrosis and rheumatic disorders in patients with hepatitis C virus infection. Br J Rheumatol. 1997;36:360–365
  38. Kallemuchikkal U, Gorevic PD. Evaluation of cryoglobulins. Arch Pathol Lab Med. 1999;123:119–125
  39. NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consens State Sci Statements. 2002;19:1–46
  40. Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature. 2005;436:967–972
  41. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic C virus infection. N Engl J Med. 2002;347:975–982
  42. Hadziyannis SJ, Sette H, Morgan TR, et al. Peginterferon-alpha 2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346–355
  43. Dienstag JL, McHutchison JG. American Gastroenterological Association technical review on the management on hepatitis C. Gastroenterology. 2006;130:231–264
  44. Russo MW, Fried MW. Side effects of therapy for chronic hepatitis C. Gastroenterology. 2003;124:1711–1719
  45. Casato M, Laganà B, Antonelli G, et al. Long-term results of therapy with interferon-alpha for type II essential mixed cryoglobulinemia. Blood. 1991;78:3142–3147
  46. Ferri C, Marzo E, Longobardo G, et al. Interferon-α in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial. Blood. 1993;81:1132–1136
  47. Mazzaro C, Pozzato G, Moretti M, et al. Long-term effects of alpha interferon therapy for type II mixed cryoglobulinemia. Haematologica. 1994;79:342–349
  48. Misiani R, Bellavita P, Fenili D, et al. Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med. 1994;330:751–756
  49. Mazzaro C, Franzin F, Tulissi P, et al. Regression of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to alpha-interferon therapy. Cancer. 1996;77:2604–2613
  50. Polzien F, Schott P, Mihm S, et al. Interferon-α treatment hepatitis C virus-associated mixed cryoglobulinemia. J Hepatol. 1997;27:63–71
  51. Donada C, Crucitti A, Donadon V, et al. Interferon-α and ribavirin combination therapy in patients with chronic hepatitis C and mixed cryoglobulinemia. Blood. 1998;92:2983–2984
  52. Cresta P, Musset L, Cacoub P, et al. Response to interferon α treatment and disappearance of cryoglobulinemia in patients infected by hepatitis C virus. Gut. 1999;45:128–134
  53. Zuckerman E, Keren D, Slobodin G, et al. Treatment of refractory, symptomatic, hepatitis C virus related mixed cryoglobulinemia with ribavirin and interferon-alpha. J Rheumatol. 2000;27:2172–2178
  54. Garini G, Allegri L, Carnevali L, et al. Interferon-alfa in combination with ribavirin as initial treatment for hepatitis C virus-associated cryoglobulinemic membranoproliferative glomerulonephritis. Am J Kidney Dis. 2001;38:E35–E39
  55. Sabry AA, Sobh MA, Sheaashaa HA, et al. Effect of combination therapy (ribavirin and interferon) in HCV-related glomerulopathy. Nephrol Dial Transplant. 2002;17:1924–1930
  56. Rossi P, Bertani T, Baio P, et al. Hepatitis C virus-related cryoglobulinemic glomerulonephritis: long-term remission after antiviral therapy. Kidney Int. 2003;63:2236–2241
  57. Mazzaro C, Zorat F, Caizzi M, et al. Treatment with peg-interferon alfa-2b and ribavirin of hepatitis C virus-associated mixed cryoglobulinemia: a pilot study. J Hepatol. 2005;42:632–638
  58. Saadoun D, Resche-Rigon M, Thibault V, et al. Antiviral therapy for hepatitis C virus-associated mixed cryoglobulinemia vasculitis: a long-term followup study. Arthritis Rheum. 2006;54:3696–3706
  59. Boonyapisit K, Katirji B. Severe exacerbation of hepatitis C-associated vasculitic neuropathy following treatment with interferon alpha: a case report and literature review. Muscle Nerve. 2002;6:909–913
  60. Otha S, Yokoyama H, Wada T, et al. Exacerbation of glomerulonephritis in subjects with chronic hepatitis C virus infection after interferon therapy. Am J Kidney Dis. 1999;33:1040–1048
  61. Bruchfeld A, Lindahl K, Stahle L, et al. Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency. Nephrol Dial Transplant. 2003;18:1573–1580
  62. Nelson DR, Rustgi V, Balan V, et al. Safety and antiviral activity of albinterferon alfa-2b in prior interferon nonresponders with chronic hepatitis C. Clin Gastroenterol Hepatol. 2009;7:212–218
  63. Gish RG, Arora S, Rajender Reddy K, et al. Virological response and safety outcomes in therapy-naïve patients treated for chronic hepatitis C with taribavirin or ribavirin in combination with pegylated interferon alfa-2a: a randomized, phase 2 study. J Hepatol. 2007;47:51–59
  64. De Francesco R, Migliaccio G. Challenges and successes in developing new therapies for hepatitis C. Nature. 2005;436:953–960
  65. Hézode C, Forestier N, Dusheiko G, et al. PROVE2 Study Team Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360:1839–1850
  66. McHutchison J, Bacon B, Gordon SC, et al. Relationships of HCV RNA responses to CPG, a TLR agonist, pharmacodynamics and patient characteristics. Hepatology. 2005;42:249A
  67. McHutchison J, Bacon BR, Gordon SC, et al. Phase 1B, randomized, double-blind, dose-escalation trial of CPG 10101 in patients with chronic hepatitis C virus. Hepatology. 2007;46:1317–1318
  68. Lamprecht P, Gause A, Gross WL. Cryoglobulinemic vasculitis. Arthritis Rheum. 1999;42:2507–2516
  69. Campise M, Tarantino A. Glomerulonephritis in mixed cryoglobulinemia: what treatment?. Nephrol Dial Transplant. 1999;14:281–283
  70. Vassilopoulos D, Calabrese LH. Hepatitis C virus infection and vasculitis (Implications of antiviral and immunosuppressive therapies). Arthritis Rheum. 2002;46:585–597
  71. Koukoulaki M, Jayne DR. Mycophenolate mofetil in anti-neutrophil cytoplasm antobodies-associated systemic vasculitis. Nephron Clin Pract. 2006;102:100–107
  72. Ramos-Casals M, Font J. Mycophenolate mofetil in patients with hepatitis C virus infection. Lupus. 2005;14(Suppl 1):S64–S72
  73. Reed MJ, Alexander GJ, Thiru S, Smith KG. Hepatitis C-associated glomerulonephritis—a novel therapeutic approach. Nephrol Dial Transplant. 2001;16:869–871
  74. Bombardieri S, Ferri C, Paleologo G, et al. Prolonged plasma exchange in the treatment of renal involvement in essential mixed cryoglobulinemia. Int J Artif Organs. 1983;6(Suppl 1):S47–S50
  75. Ramunni A, Lauletta G, Brescia P, et al. Double-filtration plasmapheresis in the treatment of leg ulcers in cryoglobulinemia. J Clin Apher. 2008;23:118–122
  76. Sansonno D, De Re V, Lauletta G, et al. Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-CD20. Blood. 2003;101:3818–3826
  77. Zaja F, De Vita S, Mazzaro C, et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood. 2003;101:3827–3834
  78. Saadoun D, Delluc A, Piette JC, Cacoub P. Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis. Curr Opin Rheumatol. 2008;20:23–28
  79. Lamprecht P, Lerin-Lozano C, Merz H, et al. Rituximab induces remission in refractory HCV associated cryoglobulinaemic vasculitis. Ann Rheum Dis. 2003;62:1230–1233
  80. Kazkaz H, Isenberg D. Anti B cell therapy (rituximab) in the treatment of autoimmune diseases. Curr Opin Pharmacol. 2004;4:398–402
  81. Roccatello D, Baldovino S, Rossi D, et al. Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinaemic glomerulonephritis. Nephrol Dial Transplant. 2004;19:3054–3061
  82. Ghijsels E, Lerut E, Vanrenterghem Y, Kuypers D. Anti-CD20 monoclonal antibody (rituximab) treatment for hepatitis C–negative therapy-resistant essential mixed cryoglobulinemia with renal and cardiac failure. Am J Kidney Dis. 2004;43:e34–e38
  83. Koukoulaki M, Abeygunasekara SC, Smith KGC, Jayne DRW. Remission of refractory hepatitis C-negative cryoglobulinaemic vasculitis after rituximab and infliximab. Nephrol Dial Transplant. 2005;20:213–216
  84. Booth A, Harper L, Hammad T, et al. Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol. 2004;15:717–721
  85. Bartolucci P, Ramanoelina J, Cohen P, et al. Efficacy of the anti-TNF-α antibody infliximab against refractory systemic vasculitides: an open pilot study on 10 patients. Rheumatology. 2002;41:1126–1132
  86. Chandesris MO, Gayet S, Schleinitz N, et al. Infliximab in the treatment of refractory vasculitis secondary to hepatitis C-associated mixed cryoglobulinemia. Rheumatology. 2004;43:532–533
  87. Galeazzi M, Bellisai F, Giannitti C, et al. Safety of cyclosporin A in HCV-infected patients. Ann N Y Acad Sci. 2007;1110:544–549
  88. Ferri C, Pietrogrande M, Cecchetti C, et al. Low-antigen-content diet in the treatment of mixed cryoglobulinemia patients. Am J Med. 1989;87:519–524
  89. Attal N, Cruccu G, Haanpää M, et al. EFNS guidlines on pharmacological treatment of neuropathic pain. Eur J Neurol. 2006;13:153–169
  90. Lo Gullo R, De Filippis L, Caliari A, Bagnato G. Successful treatment of necrotizing vasculitic lesions after infusion of iloprost in a patient with cryoglobulinemia and chronic HCV infection. Clin Exp Rheumatol. 2005;23:912–913
  91. Monti G, Saccardo F, Rinaldi G, et al. Colchicine in the treatment of mixed cryoglobulinemia. Clin Exp Rheumatol. 1995;13(Suppl 13):S197–S199
  92. Luqmani RA, Exley AR, Kitas GD, Bacon PA. Disease assessment and management of the vasculitides. QJM. 1994;87:671–678
  93. Reinhold-Keller E, Kekow J, Schnabel A, et al. Influence of disease manifestation and antineutrophil cytoplasmic antibody titer on the response to pulse cyclophosphamide therapy in patients with Wegener's granulomatosis. Arthritis Rheum. 1994;37:919–924
  94. Improving Global Outcomes. KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of Hepatitis C in chronic kidney disease (Guideline 2: treatment of HCV infection in patients with CKD). Kidney Int. 2008;73(Suppl 109):S20–S45
  95. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(Suppl 1):S1–S266

 Funding: None.

 Conflict of Interest: None of the authors has any conflicts of interest associated with the work presented in this manuscript.

 Authorship: All authors had access to the data and played a role in writing this manuscript.

PII: S0002-9343(10)00016-1

doi: 10.1016/j.amjmed.2009.09.038

The American Journal of Medicine
Volume 123, Issue 5 , Pages 400-408 , May 2010

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