UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Treatment of the mixed cryoglobulinemia syndrome

Authors
Fernando C Fervenza, MD, PhD
Michael D Leise, MD
Dario Roccatello, MD
Robert A Kyle, MD
Section Editors
Richard J Glassock, MD, MACP
Mark H Wener, MD
Deputy Editors
Albert Q Lam, MD
Monica Ramirez Curtis, MD, MPH

INTRODUCTION

The mixed cryoglobulinemia syndrome is most often induced by hepatitis C virus (HCV) infection. It can also be associated with autoimmune or lymphoproliferative disorders or, rarely, can be idiopathic. Typically, it follows a chronic, smoldering course. Infrequently, mixed cryoglobulinemia may present with a rapidly progressive or even life-threatening course. (See "Overview of cryoglobulins and cryoglobulinemia" and "Clinical manifestations and diagnosis of the mixed cryoglobulinemia syndrome (essential mixed cryoglobulinemia)".)

The main indication for immunosuppressive therapy is progressive systemic disease affecting the kidneys, nervous system, gastrointestinal tract, skin, or digits. The prognosis is variable [1-6].

The treatment of patients with the mixed cryoglobulinemia syndrome will be reviewed here. An overview of cryoglobulinemia and a discussion of the clinical manifestations and diagnosis of the mixed cryoglobulinemia syndrome are provided elsewhere. (See "Overview of cryoglobulins and cryoglobulinemia" and "Clinical manifestations and diagnosis of the mixed cryoglobulinemia syndrome (essential mixed cryoglobulinemia)".)

GENERAL APPROACH TO THERAPY

Prior to the discovery of the association with hepatitis C virus (HCV), both prednisone and cytotoxic drugs (such as cyclophosphamide and chlorambucil) were often used in patients with mixed cryoglobulinemia. However, except in those patients with a rapidly progressive course, there was no clear evidence that these modalities were beneficial [3,4]. Rituximab has been gradually replacing cytotoxic drug therapy in such patients.

Rituximab is significantly more expensive than cyclophosphamide, and there are no data directly comparing rituximab with cyclophosphamide in these patients. Thus, cyclophosphamide should still be considered a therapeutic option in patients with mixed cryoglobulinemia, especially in life-threatening situations.

                          

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Wed Jan 06 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Roccatello D, Fornasieri A, Giachino O, et al. Multicenter study on hepatitis C virus-related cryoglobulinemic glomerulonephritis. Am J Kidney Dis 2007; 49:69.
  2. Gorevic 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.
  3. D'Amico G, Colasanti G, Ferrario F, Sinico RA. Renal involvement in essential mixed cryoglobulinemia. Kidney Int 1989; 35:1004.
  4. Frankel AH, Singer DR, Winearls CG, et al. Type II essential mixed cryoglobulinaemia: presentation, treatment and outcome in 13 patients. Q J Med 1992; 82:101.
  5. Bryce AH, Kyle RA, Dispenzieri A, Gertz MA. Natural history and therapy of 66 patients with mixed cryoglobulinemia. Am J Hematol 2006; 81:511.
  6. Dammacco F, Sansonno D. Therapy for hepatitis C virus-related cryoglobulinemic vasculitis. N Engl J Med 2013; 369:1035.
  7. Pietrogrande M, De Vita S, Zignego AL, et al. Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients. Autoimmun Rev 2011; 10:444.
  8. Sandri AM, Elewa U, Poterucha JJ, Fervenza FC. Treatment of hepatitis C-mediated glomerular disease. Nephron Clin Pract 2011; 119:c121.
  9. De Vita S, Quartuccio L, Isola M, et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum 2012; 64:843.
  10. Saadoun D, Resche Rigon M, Sene D, et al. Rituximab plus Peg-interferon-alpha/ribavirin compared with Peg-interferon-alpha/ribavirin in hepatitis C-related mixed cryoglobulinemia. Blood 2010; 116:326.
  11. Ferri C, Cacoub P, Mazzaro C, et al. Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: results of multicenter cohort study and review of the literature. Autoimmun Rev 2011; 11:48.
  12. Quartuccio L, Salvin S, Fabris M, et al. Disappearance of bone marrow B cell clonal expansion in patients with type II hepatitis C virus-related cryoglobulinemic glomerulonephritis after clinical efficient rituximab therapy. Ann Rheum Dis 2008; 67:1494.
  13. Quartuccio L, Fabris M, Salvin S, et al. Bone marrow B-cell clonal expansion in type II mixed cryoglobulinaemia: association with nephritis. Rheumatology (Oxford) 2007; 46:1657.
  14. Landau DA, Saadoun D, Halfon P, et al. Relapse of hepatitis C virus-associated mixed cryoglobulinemia vasculitis in patients with sustained viral response. Arthritis Rheum 2008; 58:604.
  15. Quartuccio L, De Marchi G, Fabris M, De Vita S. Development of type II mixed cryoglobulinaemic syndrome after effective and persistent hepatitis C virus eradication. Rheumatology (Oxford) 2007; 46:367.
  16. Cavallo R, Roccatello D, Menegatti E, et al. Rituximab in cryoglobulinemic peripheral neuropathy. J Neurol 2009; 256:1076.
  17. Terrier B, Krastinova E, Marie I, et al. Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey. Blood 2012; 119:5996.
  18. Sneller MC, Hu Z, Langford CA. A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-associated cryoglobulinemic vasculitis. Arthritis Rheum 2012; 64:835.
  19. Quartuccio L, Soardo G, Romano G, et al. Rituximab treatment for glomerulonephritis in HCV-associated mixed cryoglobulinaemia: efficacy and safety in the absence of steroids. Rheumatology (Oxford) 2006; 45:842.
  20. 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.
  21. Roccatello D, Baldovino S, Rossi D, et al. Rituximab as a therapeutic tool in severe mixed cryoglobulinemia. Clin Rev Allergy Immunol 2008; 34:111.
  22. Petrarca A, Rigacci L, Caini P, et al. Safety and efficacy of rituximab in patients with hepatitis C virus-related mixed cryoglobulinemia and severe liver disease. Blood 2010; 116:335.
  23. 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.
  24. Basse G, Ribes D, Kamar N, et al. Rituximab therapy for de novo mixed cryoglobulinemia in renal transplant patients. Transplantation 2005; 80:1560.
  25. Visentini M, Ludovisi S, Petrarca A, et al. A phase II, single-arm multicenter study of low-dose rituximab for refractory mixed cryoglobulinemia secondary to hepatitis C virus infection. Autoimmun Rev 2011; 10:714.
  26. Landau DA, Scerra S, Sene D, et al. Causes and predictive factors of mortality in a cohort of patients with hepatitis C virus-related cryoglobulinemic vasculitis treated with antiviral therapy. J Rheumatol 2010; 37:615.
  27. Valbonesi M, Florio G, Montani F, Mosconi L. A method for the study of cryoglobulin solubilization curves at 37 degrees C. Preliminary studies and application to plasma exchange in cryoglobulinemic syndromes. Int J Artif Organs 1983; 6:87.
  28. Ramos-Casals M, Robles A, Brito-Zerón P, et al. Life-threatening cryoglobulinemia: clinical and immunological characterization of 29 cases. Semin Arthritis Rheum 2006; 36:189.
  29. Rockx MA, Clark WF. Plasma exchange for treating cryoglobulinemia: a descriptive analysis. Transfus Apher Sci 2010; 42:247.
  30. Madore F, Lazarus JM, Brady HR. Therapeutic plasma exchange in renal diseases. J Am Soc Nephrol 1996; 7:367.
  31. Guillevin L, Pagnoux C. Indications of plasma exchanges for systemic vasculitides. Ther Apher Dial 2003; 7:155.
  32. Szczepiorkowski ZM, Winters JL, Bandarenko N, et al. Guidelines on the use of therapeutic apheresis in clinical practice--evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher 2010; 25:83.
  33. Campise M, Tarantino A. Glomerulonephritis in mixed cryoglobulinaemia: what treatment? Nephrol Dial Transplant 1999; 14:281.
  34. Evans TW, Nicholls AJ, Shortland JR, et al. Acute renal failure in essential mixed cryoglobulinemia: precipitation and reversal by plasma exchange. Clin Nephrol 1984; 21:287.
  35. Mazzi G, Raineri A, Zucco M, et al. Plasma-exchange in chronic peripheral neurological disorders. Int J Artif Organs 1999; 22:40.
  36. Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis 2009; 68:310.
  37. AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology 2015; 62:932.
  38. Dammacco F, Sansonno D, Han JH, et al. Natural interferon-alpha versus its combination with 6-methyl-prednisolone in the therapy of type II mixed cryoglobulinemia: a long-term, randomized, controlled study. Blood 1994; 84:3336.
  39. 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.
  40. Lunel F, Musset L, Cacoub P, et al. Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology 1994; 106:1291.
  41. Ferri C, Marzo E, Longombardo G, et al. Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial. Blood 1993; 81:1132.
  42. Misiani R, Bellavita P, Fenili D, et al. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 1992; 117:573.
  43. Johnson RJ, Willson R, Yamabe H, et al. Renal manifestations of hepatitis C virus infection. Kidney Int 1994; 46:1255.
  44. 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.
  45. Poynard T, Bedossa P, Chevallier M, et al. A comparison of three interferon alfa-2b regimens for the long-term treatment of chronic non-A, non-B hepatitis. Multicenter Study Group. N Engl J Med 1995; 332:1457.
  46. Poynard T, Leroy V, Cohard M, et al. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 1996; 24:778.
  47. Casato M, Agnello V, Pucillo LP, et al. Predictors of long-term response to high-dose interferon therapy in type II cryoglobulinemia associated with hepatitis C virus infection. Blood 1997; 90:3865.
  48. Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 1992; 327:1490.
  49. Gragnani L, Fognani E, Piluso A, et al. Long-term effect of HCV eradication in patients with mixed cryoglobulinemia: a prospective, controlled, open-label, cohort study. Hepatology 2015; 61:1145.
  50. 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.
  51. 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.
  52. Saadoun D, Resche Rigon M, Thibault V, et al. Peg-IFNα/ribavirin/protease inhibitor combination in hepatitis C virus associated mixed cryoglobulinemia vasculitis: results at week 24. Ann Rheum Dis 2014; 73:831.
  53. Saadoun D, Resche Rigon M, Pol S, et al. PegIFNα/ribavirin/protease inhibitor combination in severe hepatitis C virus-associated mixed cryoglobulinemia vasculitis. J Hepatol 2015; 62:24.
  54. Cornella SL, Stine JG, Kelly V, et al. Persistence of mixed cryoglobulinemia despite cure of hepatitis C with new oral antiviral therapy including direct-acting antiviral sofosbuvir: A case series. Postgrad Med 2015; 127:413.
  55. La Civita L, Zignego AL, Lombardini F, et al. Exacerbation of peripheral neuropathy during alpha-interferon therapy in a patient with mixed cryoglobulinemia and hepatitis B virus infection. J Rheumatol 1996; 23:1641.
  56. Harlé JR, Disdier P, Pelletier J, et al. Dramatic worsening of hepatitis C virus-related cryoglobulinemia subsequent to treatment with interferon alfa. JAMA 1995; 274:126.
  57. Friedman G, Mehta S, Sherker AH. Fatal exacerbation of hepatitis C-related cryoglobulinemia with interferon-alpha therapy. Dig Dis Sci 1999; 44:1364.
  58. Raanani P, Ben-Bassat I. Immune-mediated complications during interferon therapy in hematological patients. Acta Haematol 2002; 107:133.
  59. Batisse D, Karmochkine M, Jacquot C, et al. Sustained exacerbation of cryoglobulinaemia-related vasculitis following treatment of hepatitis C with peginterferon alfa. Eur J Gastroenterol Hepatol 2004; 16:701.
  60. Sawabe T, Uenotsuchi T, Imafuku S, et al. Remission of hepatitis B virus-related vasculitis with lamivudine. Ann Intern Med 2004; 140:672.
  61. Stecevic V, Pevzner MM, Gordon SC. Successful treatment of hepatitis B-associated vasculitis with lamivudine. J Clin Gastroenterol 2003; 36:451.
  62. Kawakami T, Ooka S, Mizoguchi M, et al. Remission of hepatitis B virus-related cryoglobulinemic vasculitis with entecavir. Ann Intern Med 2008; 149:911.
  63. Enomoto M, Nakanishi T, Ishii M, et al. Entecavir to treat hepatitis B-associated cryoglobulinemic vasculitis. Ann Intern Med 2008; 149:912.
  64. Boglione L, D'Avolio A, Cariti G, Di Perri G. Telbivudine in the treatment of hepatitis B-associated cryoglobulinemia. J Clin Virol 2013; 56:167.
  65. Pasquet F, Combarnous F, Macgregor B, et al. Safety and efficacy of rituximab treatment for vasculitis in hepatitis B virus-associated type II cryoglobulinemia: a case report. J Med Case Rep 2012; 6:39.
  66. Saadoun D, Pineton de Chambrun M, Hermine O, et al. Using rituximab plus fludarabine and cyclophosphamide as a treatment for refractory mixed cryoglobulinemia associated with lymphoma. Arthritis Care Res (Hoboken) 2013; 65:643.
  67. Michot JM, Canioni D, Driss H, et al. Antiviral therapy is associated with a better survival in patients with hepatitis C virus and B-cell non-Hodgkin lymphomas, ANRS HC-13 lympho-C study. Am J Hematol 2015; 90:197.
  68. 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.
  69. Retamozo S, Díaz-Lagares C, Bosch X, et al. Life-Threatening Cryoglobulinemic Patients With Hepatitis C: Clinical Description and Outcome of 279 Patients. Medicine (Baltimore) 2013.
  70. Tarantino A, Campise M, Banfi G, et al. Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int 1995; 47:618.
  71. Lauletta G, Russi S, Conteduca V, et al. Impact of Cryoglobulinemic Syndrome on the Outcome of Chronic Hepatitis C Virus Infection: A 15-Year Prospective Study. Medicine (Baltimore) 2013.
  72. Levine JW, Gota C, Fessler BJ, et al. Persistent cryoglobulinemic vasculitis following successful treatment of hepatitis C virus. J Rheumatol 2005; 32:1164.
  73. Terrier B, Carrat F, Krastinova E, et al. Prognostic factors of survival in patients with non-infectious mixed cryoglobulinaemia vasculitis: data from 242 cases included in the CryoVas survey. Ann Rheum Dis 2013; 72:374.
  74. Tarantino A, Moroni G, Banfi G, et al. Renal replacement therapy in cryoglobulinaemic nephritis. Nephrol Dial Transplant 1994; 9:1426.
  75. Hiesse C, Bastuji-Garin S, Santelli G, et al. Recurrent essential mixed cryoglobulinemia in renal allografts. Report of two cases and review of the literature. Am J Nephrol 1989; 9:150.