Highlights & Basics
- Cryoglobulinemia may be asymptomatic or present acutely.
- Mixed cryoglobulinemia (MC) is the most common type, and it is strongly associated with chronic hepatitis C virus (HCV) infection.
- Clinical presentation includes a triad of purpura, weakness, and arthralgia. Multisystemic involvement may include the kidneys, liver, and nervous system.
- Diagnosis is based on clinical and laboratory findings. Leukocytoclastic vasculitis is the histologic hallmark of MC.
- Management of MC secondary to chronic HCV infection includes viral eradication strategies in addition to immunosuppression.
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Citations
Ferri C. Mixed cryoglobulinemia. Orphanet J Rare Dis. 2008 Sep 16;3:25.[Abstract][Full Text]
Roccatello D, Saadoun D, Ramos-Casals M, et al. Cryoglobulinaemia. Nat Rev Dis Primers. 2018 Aug 2;4(1):11.[Abstract]
American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. Oct 2022 [internet publication].[Full Text]
Quartuccio L, Bortoluzzi A, Scirè CA, et al. Management of mixed cryoglobulinemia with rituximab: evidence and consensus-based recommendations from the Italian Study Group of Cryoglobulinemia (GISC). Clin Rheumatol. 2023 Feb;42(2):359-70.[Abstract][Full Text]
Montero N, Favà A, Rodriguez E, et al. Treatment for hepatitis C virus-associated mixed cryoglobulinaemia. Cochrane Database Syst Rev. 2018 May 7;(5):CD011403.[Abstract][Full Text]
Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work Group. KDIGO 2022 clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int. 2022 Dec;102(6s):S129-205.[Full Text]
1. Dispenzieri A, Gorevic PD. Cryoglobulinemia. Hematol Oncol Clin North Am. 1999 Dec;13(6):1315-49.[Abstract]
2. Tedeschi A, Barate C, Minola E, et al. Cryoglobulinemia. Blood Rev. 2007 Jul;21(4):183-200. [Abstract]
3. Gorevic P, Kassab H, Levo Y, et al. Mixed cryoglobulinemia: clinical aspects and long term follow-up in 40 patients. Am J Med. 1980 Aug;69(2):287-308.[Abstract]
4. Ferri C. Mixed cryoglobulinemia. Orphanet J Rare Dis. 2008 Sep 16;3:25.[Abstract][Full Text]
5. Brouet JC, Clauvel JP, Danon F, et al. Biological and clinical significance of cryoglobulins. A report of 86 cases. Am J Med. 1974 Nov;57(5):775-88.[Abstract]
6. Silva F, Pinto C, Barbosa A, et al. New insights in cryoglobulinemic vasculitis. J Autoimmun. 2019 Dec;105:102313.[Abstract]
7. Roccatello D, Saadoun D, Ramos-Casals M, et al. Cryoglobulinaemia. Nat Rev Dis Primers. 2018 Aug 2;4(1):11.[Abstract]
8. Monti G, Saccardo F, Castelnovo L, et al. Prevalence of mixed cryoglobulinaemia syndrome and circulating cryoglobulins in a population-based survey: the origgio study. Autoimmun Rev. 2014 Jun;13(6):609-14.[Abstract]
9. Trejo O, Ramos-Casals M, Garcia-Carrasco M, et al. Cryoglobulinemia: study of etiologic factors and clinical and immunologic features in 443 patients from a single center. Medicine (Baltimore). 2001 Jul;80(4):252-62.[Abstract]
10. Sise ME, Bloom AK, Wisocky J, et al. Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents. Hepatology. 2016 Feb;63(2):408-17.[Abstract][Full Text]
11. Misiani R, Bellavita P, Fenili D, et al. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med. 1992 Oct 1;117(7):573-7.[Abstract]
12. Sansonno D, Dammacco F. Hepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations. Lancet Infect Dis. 2005 Apr;5(4):227-36.[Abstract]
13. Ramos-Casals M, Stone JH, Cid MC, et al. The cryoglobulinaemias. Lancet. 2012 Jan 28;379(9813):348-60.[Abstract]
14. Dammacco F, Sansonno D. Mixed cryoglobulinemia as a model of systemic vasculitis. Clin Rev Allergy Immunol. 1997 Spring;15(1):97-119.[Abstract]
15. Ferri C, Sebastiani M, Giuggioli D, et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum. 2004 Jun;33(6):355-74.[Abstract]
16. Dammacco F, Lauletta G, Vacca A. The wide spectrum of cryoglobulinemic vasculitis and an overview of therapeutic advancements. Clin Exp Med. 2023 Jun;23(2):255-72.[Abstract][Full Text]
17. Mascia MT, Ferrari D, Campioli D, et al. Non HCV-related mixed cryoglobulinemia. Dig Liver Dis. 2007 Sep;39(suppl 1):S61-4.[Abstract]
18. Napodano C, Gulli F, Rapaccini GL, et al. Cryoglobulins: Identification, classification, and novel biomarkers of mysterious proteins. Adv Clin Chem. 2021;104:299-340.[Abstract][Full Text]
19. Kuroda Y, Kuroki A, Kikuchi S, et al. A critical role for sialylation in cryoglobulin activity of murine IgG3 monoclonal antibodies. J Immunol. 2005 Jul 15;175(2):1056-61.[Abstract][Full Text]
20. 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 Feb;88(2):115-26.[Abstract]
21. Ghobrial IM, Gertz MA, Fonseca R. Waldenstrom macroglobulinaemia. Lancet Oncol. 2003 Nov;4(11):679-85.[Abstract]
22. Wintrobe M, Buell M. Hyperproteinemia associated with multiple myeloma. Bull Johns Hopkins Hosp. 1933;52:156-65.
23. Ferri C, Mascia M. Cryoglobulinemic vasculitis. Curr Opin Rheumatol. 2006 Jan;18(1):54-63.[Abstract]
24. Suresh E. Diagnostic approach to patients with suspected vasculitis. Postgrad Med J. 2006 Aug;82(970):483-8.[Abstract][Full Text]
25. Vitali C, Ferri C, Nasti P, et al. Hypercomplementaemia as a marker of the evolution from benign to malignant B cell proliferation in patients with type II mixed cryoglobulinaemia. Br J Rheumatol. 1994 Aug;33(8):791-2.[Abstract]
26. Lamprecht P, Moosig F, Gause A, et al. Immunological and clinical follow up of hepatitis C virus associated cryoglobulinaemic vasculitis. Ann Rheum Dis. 2001 Apr;60(4):385-90.[Abstract][Full Text]
27. Ramos-Casals M, Loustaud-Ratti V, De Vita S, et al. Sjogren syndrome associated with hepatitis C virus: a multicenter analysis of 137 cases. Medicine (Baltimore). 2005 Mar;84(2):81-9.[Abstract]
28. Leone N, Pellicano R, Ariata Maiocco I, et al. Mixed cryoglobulinemia and chronic hepatitis C virus infection: the rheumatic manfestations. J Med Virol. 2002 Feb;66(2):200-3. [Abstract]
29. Lormeau C, Falgarone G, Roulot D, et al. Rheumatologic manifestations of chronic hepatitis C infection. Joint Bone Spine. 2006 Dec;73(6):633-8.[Abstract]
30. Bombardieri M, Alessandri C, Labbadia G, et al. Role of anti-cyclic citrullinated peptide antibodies in discriminating patients with rheumatoid arthritis from patients with chronic hepatitis C infection-associated polyarticular involvement. Arthritis Res Ther. 2004;6(2):R137-41. [Abstract][Full Text]
31. Sidana S, Rajkumar SV, Dispenzieri A, et al. Clinical presentation and outcomes of patients with type 1 monoclonal cryoglobulinemia. Am J Hematol. 2017 Jul;92(7):668-73.[Abstract][Full Text]
32. Ammendola A, Sampaolo S, Ambrosone L, et al. Peripheral neuropathy in hepatitis-related mixed cryoglobulinemia: electrophysiologic follow-up study. Muscle Nerve. 2005 Mar;31(3):382-5.[Abstract]
33. Gemignani F, Brindani F, Alfieri S, et al. Clinical spectrum of cryoglobulinaemic neuropathy. J Neurol Neurosurg Psychiatry. 2005 Oct;76(10):1410-4.[Abstract][Full Text]
34. Casato M, Saadoun D, Marchetti A, et al. Central nervous system involvement in hepatitis C virus cryoglobulinemia vasculitis: a multicenter case-control study using magnetic resonance imaging and neurophysiological tests. J Rheumatol. 2005 Mar;32(3):484-8.[Abstract]
35. Saadoun D, Landau DA, Calabrese LH, et al. Hepatitis C-associated mixed cryoglobulinemia: a crossroad between autoimmunity and lymphoproliferation. Rheumatology (Oxford). 2007 Aug;46(8):1234-42. [Abstract][Full Text]
36. Tarantino A, Campise M, Banfi G, et al. Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int. 1995 Feb;47(2):618-23.[Abstract][Full Text]
37. Beddhu S, Bastacky S, Johnson JP, et al. The clinical and morphologic spectrum of renal cryoglobulinemia. Medicine (Baltimore). 2002 Sep;81(5):398-409.[Abstract]
38. Kay J, McCluskey RT. Case records of the Massachusetts General Hospital. Case 31-2005. A 60-year-old man with skin lesions and renal insufficiency. N Engl J Med. 2005 Oct 13;353(15):1605-13.[Abstract]
39. D'Amico G. Renal involvement in hepatitis C infection: cryoglobulinemic glomerulonephritis. Kidney Int. 1998 Aug;54(2):650-71.[Abstract][Full Text]
40. Della Rossa A, Tavoni A, Bombardieri S. Hyperviscosity syndrome in cryoglobulinemia: clinical aspects and therapeutic considerations. Semin Thromb Hemost. 2003 Oct;29(5):473-7.[Abstract]
41. Chan AO, Lau JS, Chan CH, et al. Cryoglobulinaemia: clinical and laboratory perspectives. Hong Kong Med J. 2008 Feb;14(1):55-9.[Abstract][Full Text]
42. Amdo TD, Welker JA. An approach to the diagnosis and treatment of cryofibrinogenemia. Am J Med. 2004 Mar 1;116(5):332-7.[Abstract]
43. Shah H, Bilodeau M, Burak KW, et al. The management of chronic hepatitis C: 2018 guideline update from the Canadian Association for the Study of the Liver. CMAJ. 2018 Jun 4;190(22):E677-87.[Abstract][Full Text]
44. European Association for the Study of the Liver, Clinical Practice Guidelines Panel: Chair:, EASL Governing Board representative:, et al. EASL recommendations on treatment of hepatitis C: final update of the series(☆). J Hepatol. 2020 Nov;73(5):1170-218.[Abstract][Full Text]
45. Cacoub P, Desbois AC, Comarmond C, et al. Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis. Gut. 2018 Nov;67(11):2025-34.[Abstract]
46. El-Serag HB, Christie IC, Puenpatom A, et al. The effects of sustained virological response to direct-acting anti-viral therapy on the risk of extrahepatic manifestations of hepatitis C infection. Aliment Pharmacol Ther. 2019 Jun;49(11):1442-7. [Abstract]
47. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. Oct 2022 [internet publication].[Full Text]
48. Gragnani L, Fabbrizzi A, Triboli E, et al. Triple antiviral therapy in hepatitis C virus infection with or without mixed cryoglobulinaemia: a prospective, controlled pilot study. Dig Liver Dis. 2014 Sep;46(9):833-7.[Abstract]
49. Saadoun D, Resche Rigon M, Pol S, et al. PegIFNalfa/ribavirin/protease inhibitor combination in severe hepatitis C virus-associated mixed cryoglobulinemia vasculitis. J Hepatol. 2015 Jan;62(1):24-30.[Abstract]
50. 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 May;127(4):413-7. [Abstract]
51. Emery JS, Kuczynski M, La D, et al. Efficacy and safety of direct acting antivirals for the treatment of mixed cryoglobulinemia. Am J Gastroenterol. 2017 Aug;112(8):1298-308.[Abstract]
52. Saadoun D, Thibault V, Si Ahmed SN, et al. Sofosbuvir plus ribavirin for hepatitis C virus-associated cryoglobulinaemia vasculitis: VASCUVALDIC study. Ann Rheum Dis. 2016 Oct;75(10):1777-82.[Abstract]
53. Gragnani L, Visentini M, Fognani E, et al. Prospective study of guideline-tailored therapy with direct-acting antivirals for hepatitis C virus-associated mixed cryoglobulinemia. Hepatology. 2016 Nov;64(5):1473-82. [Abstract][Full Text]
54. Bonacci M, Lens S, Mariño Z, et al. Long-term outcomes of patients with HCV-associated cryoglobulinemic vasculitis after virologic cure. Gastroenterology. 2018 Aug;155(2):311-5;e6. [Abstract]
55. Muchtar E, Magen H, Gertz MA. How I treat cryoglobulinemia. Blood. 2017 Jan 19;129(3):289-98.[Abstract][Full Text]
56. Tavoni A, Mosca M, Ferri C, et al. Guidelines for the management of essential mixed cryoglobulinemia. Clin Exp Rheumatol. 1995 Nov-Dec;13(suppl 13):S191-5.[Abstract]
57. Saadoun D, Delluc A, Piette JC, et al. Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis. Curr Opin Rheumatol. 2008 Jan;20(1):23-8. [Abstract]
58. 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 Mar;64(3):843-53.[Abstract][Full Text]
59. Quartuccio L, Bortoluzzi A, Scirè CA, et al. Management of mixed cryoglobulinemia with rituximab: evidence and consensus-based recommendations from the Italian Study Group of Cryoglobulinemia (GISC). Clin Rheumatol. 2023 Feb;42(2):359-70.[Abstract][Full Text]
60. Montero N, Favà A, Rodriguez E, et al. Treatment for hepatitis C virus-associated mixed cryoglobulinaemia. Cochrane Database Syst Rev. 2018 May 7;(5):CD011403.[Abstract][Full Text]
61. Colantuono S, Mitrevski M, Yang B, et al. Efficacy and safety of long-term treatment with low-dose rituximab for relapsing mixed cryoglobulinemia vasculitis. Clin Rheumatol. 2017 Mar;36(3):617-23. [Abstract]
62. Visentini M, Tinelli C, Colantuono S, et al. Efficacy of low-dose rituximab for the treatment of mixed cryoglobulinemia vasculitis: phase II clinical trial and systematic review. Autoimmun Rev. 2015 Oct;14(10):889-96.[Abstract]
63. Saleh F, Ko HH, Davis JE, et al. Fatal hepatitis C associated fibrosing cholestatic hepatitis as a complication of cyclophosphamide and corticosteroid treatment of active glomerulonephritis. Ann Hepatol. 2007 Jul-Sep;6(3):186-9.[Abstract][Full Text]
64. Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work Group. KDIGO 2022 clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int. 2022 Dec;102(6s):S129-205.[Full Text]
65. Scarpato S, Tirri E, Naclerio C, et al. Plasmapheresis in cryoglobulinemic neuropathy: a clinical study. Dig Liver Dis. 2007 Sep;39(suppl 1):S136-7.[Abstract]
66. Stone MJ. Waldenstrom's macroglobulinemia: hyperviscosity syndrome and cryoglobulinemia. Clin Lymphoma Myeloma. 2009 Mar;9(1):97-9. [Abstract]
67. Thiel J, Peters T, Mas Marques A, et al. Kinetics of hepatitis C (HCV) viraemia and quasispecies during treatment of HCV associated cryoglobulinaemia with pulse cyclophosphamide. Ann Rheum Dis. 2002 Sep;61(9):838-41.[Abstract][Full Text]
68. Lamprecht P, Gause A, Gross WL. Cryoglobulinemic vasculitis resistant to intermittent intravenous pulse cyclophosphamide therapy. Scand J Rheumatol. 2000;29(3):201-2.[Abstract]
69. Michael AB, Lawes M, Kamalarajan M, et al. Cryoglobulinaemia as an acute presentation of Waldenstrom's macroglobulinaemia. Br J Haematol. 2004 Mar;124(5):565.[Abstract]
70. Ferri C, Mannini L, Bartoli V, et al. Blood viscosity and filtration abnormalities in mixed cryoglobulinemia patients. Clin Exp Rheumatol. 1990 May-Jun;8(3):271-81.[Abstract]
71. Antonelli A, Ferri C, Fallahi P, et al. Thyroid involvement in patients with overt HCV-related mixed cryoglobulinaemia. QJM. 2004 Aug;97(8):499-506.[Abstract][Full Text]
