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Understanding the Cryoglobulinemias

  • Vasculitis (L Espinoza, Section Editor)
  • Published:
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Abstract

Purpose of the Review

Cryoglobulins are immunoglobulins with the ability to precipitate at temperatures <37 °C. They are related to hematological disorders, infections [especially hepatitis C virus (HCV)], and autoimmune diseases. In this article, the state of the art on Cryoglobulinemic Vasculitis (CV), in a helpful and schematic way, with a special focus on HCV related Mixed Cryoglobulinemia treatment are reviewed.

Recent Findings

Direct – acting antivirals (DAA) against HCV have emerged as an important key in HCV treatment to related Cryoglobulinemic Vasculitis, and should be kept in mind as the initial treatment in non–severe manifestations. On the other hand, a recent consensus panel has published their recommendations for treatment in severe and life threatening manifestations of Mixed Cryoglobulinemias.

Summary

HCV-Cryoglobulinemic vasculitis is the most frequent form of CV. There are new treatment options in HCV-CV with DAA, with an important number of patients achieving complete response and sustained virologic response (SVR). In cases of severe forms of CV, treatment with Rituximab and PLEX are options. The lack of data on maintenance therapy could impulse future studies in this setting.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Ferri C, Zignego AL, Pileri SA. Cryoglobulins. J Clin Pathol [Internet]. 2002;55(1):4–13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11825916.

  2. Ferri C. Mixed cryoglobulinemia. Orphanet Journal of Rare Diseases. 2008;3:1–17.

  3. Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet (London, England) [Internet]. 2012;379(9813):348–60 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21868085.

    CAS  Google Scholar 

  4. Sargur R, White P, Egner W. Cryoglobulin evaluation: best practice? Ann Clin Biochem [Internet]. 2010;47(Pt 1):8–16 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20040797.

    CAS  Google Scholar 

  5. Maire MA, Mittey M, Lambert PH. The presence of cryoprecipitable immunoglobulins in normal human sera may reflect specific molecular interactions. Autoimmunity [Internet]. 1989;2(2):155–64 Available from: http://www.ncbi.nlm.nih.gov/pubmed/2491599.

    CAS  Google Scholar 

  6. Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M. Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med. 1974;57(5):775–88.

    CAS  PubMed  Google Scholar 

  7. •• Roccatello D, Saadoun D, Ramos-Casals M, Tzioufas AG, Fervenza FC, Cacoub P, et al. Cryoglobulinaemia. Nat Rev Dis Prim [Internet]. 2018;4(1):11 Available from: http://www.nature.com/articles/s41572-018-0009-4. An excellent, extensive and recent review of cryoglobulinemias.

    Google Scholar 

  8. Tissot JD, Schifferli JA, Hochstrasser DF, Pasquali C, Spertini F, Clément F, et al. Two-dimensional polyacrylamide gel electrophoresis analysis of cryoglobulins and identification of an IgM-associated peptide. J Immunol Methods. 1994;173(1):63–75.

    CAS  PubMed  Google Scholar 

  9. Muchtar E, Magen H, Gertz MA. How I Treat cryoglobulinemia. Blood [Internet]. 2017;129(3):289–98 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27799164.

    CAS  Google Scholar 

  10. Desbois AC, Cacoub P, Saadoun D. Cryoglobulinemia: An update in 2019. Joint Bone Spine [Internet]. 2019 Feb 4; Available from: http://www.ncbi.nlm.nih.gov/pubmed/30731128.

  11. Lunel F, Musset L, Cacoub P, Frangeul L, Cresta P, Perrin M, et al. Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology. 1994;106:1291–300.

    CAS  PubMed  Google Scholar 

  12. Ferri C, Greco F, Longombardo G, Palla P, Moretti A, Marzo E, et al. Antibodies to hepatitis C virus in patients with mixed cryoglobulinemia. Arthritis Rheum. 1991;34:1606–10.

    CAS  PubMed  Google Scholar 

  13. Cacoub P, Poynard T, Ghillani P, Charlotte F, Olivi M, Charles Piette J, et al. Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC group. Multidepartment virus C. Arthritis Rheum. 1999;42(9):2204–12.

    CAS  PubMed  Google Scholar 

  14. Ramos-Casals M, Trejo O, García-Carrasco M, Cervera R, Font J. Mixed cryoglobulinemia: new concepts. Lupus. 2000;9:83–91.

    CAS  PubMed  Google Scholar 

  15. Adinolfi LE, Utili R, Attanasio V, Zampino R, Ragone E, Tripodi MF, et al. Epidemiology, clinical spectrum and prognostic value of mixed cryoglobulinaemia in hepatitis C virus patients: a prospective study. Ital J Gastroenterol. 1996;28:1–9.

    CAS  PubMed  Google Scholar 

  16. Kayali Z, Buckwold VE, Zimmerman B, Schmidt WN. Hepatitis C, cryoglobulinemia, and cirrhosis: a meta- analysis. Hepatology. 2002;36:978–85.

    PubMed  Google Scholar 

  17. Saadoun D, Asselah T, Resche-Rigon M, Charlotte F, Bedossa P, Valla D, et al. Cryoglobulinemia is associated with steatosis and fibrosis in chronic hepatitis C. Hepatology. 2006;43:1337–45.

    CAS  PubMed  Google Scholar 

  18. Bonnet F, Pineau J-J, Taupin J-L, Feyler A, Bonarek M, de Witte S, et al. Prevalence of cryoglobulinemia and serological markers of autoimmunity in human immunodeficiency virus infected individuals: a cross-sectional study of 97 patients. J Rheumatol. 2003;30(9):2005–10.

    PubMed  Google Scholar 

  19. Ferri C, Sebastiani M, Giuggioli D, Cazzato M, Longombardo G, Antonelli A, et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum. 2004;33(6):355–74.

    PubMed  Google Scholar 

  20. García-Carrasco M, et al. Cryoglobulinemia in systemic lupus erythematosus: prevalence and clinical characteristics in a series of 122 patients. Semin Arthritis Rheum 3. 2001;30:366–73.

    Google Scholar 

  21. Tzioufas AG, Manoussakis MN, Costello R, Silis M, Papadopoulos NM, Moutsopoulos HM. Cryoglobulinemia in autoimmune rheumatic diseases. Evidence of circulating monoclonal cryoglobulins in patients with primary Sjögren’s syndrome. Arthritis Rheum. 1986;29:1098–104.

    CAS  PubMed  Google Scholar 

  22. Brito-Zerón P, et al. Sjögren syndrome. Nat Rev Dis Prim. 2016;(2):16047.

  23. Saadoun D, Landau DA, Calabrese LH, Cacoub PP. Hepatitis C-associated mixed cryoglobulinaemia: a crossroad between autoimmunity and lymphoproliferation. Rheumatology (Oxford) [Internet]. 2007;46(8):1234–42 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17566058.

    CAS  Google Scholar 

  24. Monti G, Pioltelli P, Saccardo F, Campanini M, Candela M, Cavallero G, 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 [Internet]. 2005;165(1):101–5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15642884.

    Google Scholar 

  25. Andersen BR, Tesar JT, Schmid FR, Haisty WK, Hartz WH. Biological and physical properties of a human m-cryoglobulin and its monomer subunit. Clin Exp Immunol [Internet]. 1971;9(6):795–807 Available from: http://www.ncbi.nlm.nih.gov/pubmed/5003445.

    CAS  Google Scholar 

  26. Trendelenburg M, Schifferli JA. Cryoglobulins in chronic hepatitis C virus infection. Clin Exp Immunol [Internet]. 2003;133(2):153–5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12869018.

    CAS  Google Scholar 

  27. Grey HM, Kohler PF. Cryoimmunoglobulins. Semin Hematol [Internet]. 1973;10(2):87–112 Available from: http://www.ncbi.nlm.nih.gov/pubmed/4633223.

    CAS  Google Scholar 

  28. Di Stasio E, Bizzarri P, Casato M, Galtieri A, Fiorilli M, Pucillo LP. Cl- regulates cryoglobulin structure: a new hypothesis for the physiopathological mechanism of temperature non-dependent cryoprecipitation. Clin Chem Lab Med [Internet]. 2004;42(6):614–20 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15259377.

    Google Scholar 

  29. Qi M, Steiger G, Schifferli JA. A calcium-dependent cryoglobulin IgM kappa/polyclonal IgG. J Immunol [Internet]. 1992;149(7):2345–51 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1527381.

    CAS  Google Scholar 

  30. Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R, et al. Binding of hepatitis C virus to CD81. Science [Internet]. 1998;282(5390):938–41 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9794763.

    CAS  Google Scholar 

  31. Charles ED, Dustin LB. Hepatitis C virus-induced cryoglobulinemia. Kidney Int [Internet]. 2009;76(8):818–24 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19606079.

    Google Scholar 

  32. Ito M, Murakami K, Suzuki T, Mochida K, Suzuki M, Ikebuchi K, et al. Enhanced expression of lymphomagenesis-related genes in peripheral blood B cells of chronic hepatitis C patients. Clin Immunol [Internet]. 2010;135(3):459–65 Available from: https://linkinghub.elsevier.com/retrieve/pii/S1521661610000434.

    CAS  Google Scholar 

  33. Charles ED, Green RM, Marukian S, Talal AH, Lake-Bakaar GV, Jacobson IM, et al. Clonal expansion of immunoglobulin M+CD27+ B cells in HCV-associated mixed cryoglobulinemia. Blood [Internet]. 2008;111(3):1344–56 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17942751.

    CAS  Google Scholar 

  34. Fabris M, Quartuccio L, Sacco S, De Marchi G, Pozzato G, Mazzaro C, et al. B-Lymphocyte stimulator (BLyS) up-regulation in mixed cryoglobulinaemia syndrome and hepatitis-C virus infection. Rheumatology (Oxford) [Internet]. 2007;46(1):37–43 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16735452.

    CAS  Google Scholar 

  35. Lake-Bakaar G, Jacobson I, Talal A. B cell activating factor (BAFF) in the natural history of chronic hepatitis C virus liver disease and mixed cryoglobulinaemia. Clin Exp Immunol [Internet]. 2012;170(2):231–7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23039894.

    CAS  Google Scholar 

  36. De Vita S, De Re V, Gasparotto D, Ballarè M, Pivetta B, Ferraccioli G, et al. Oligoclonal non-neoplastic B cell expansion is the key feature of type II mixed cryoglobulinemia: clinical and molecular findings do not support a bone marrow pathologic diagnosis of indolent B cell lymphoma. Arthritis Rheum [Internet]. 2000;43(1):94–102 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10643704.

    Google Scholar 

  37. Dammacco F, Lauletta G, Russi S, Leone P, Tucci M, Manno C, et al. Clinical practice: hepatitis C virus infection, cryoglobulinemia and cryoglobulinemic vasculitis. Clin Exp Med [Internet]. 2019;19(1):1–21 Available from: http://www.ncbi.nlm.nih.gov/pubmed/30430284.

    CAS  Google Scholar 

  38. Lauletta G, Russi S, Conteduca V, Sansonno L. Hepatitis C virus infection and mixed cryoglobulinemia. Clin Dev Immunol [Internet]. 2012;2012:502156 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22844322.

    Google Scholar 

  39. Ferri C, Sebastiani M, Giuggioli D, Colaci M, Fallahi P, Piluso A, et al. Hepatitis C virus syndrome: A constellation of organ- and non-organ specific autoimmune disorders, B-cell non-Hodgkin’s lymphoma, and cancer. World J Hepatol [Internet]. 2015;7(3):327–43 Available from: http://www.wjgnet.com/1948-5182/full/v7/i3/327.htm.

    Google Scholar 

  40. Lauletta G, Russi S, Conteduca V, Sansonno L, Dammacco F, Sansonno D. Impact of Cryoglobulinemic Syndrome on the Outcome of Chronic Hepatitis C Virus Infection: A 15-Year Prospective Study. Medicine (Baltimore) [Internet]. 2013;92(5):245–56 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23982056.

    CAS  Google Scholar 

  41. Giordano TP, Henderson L, Landgren O, Chiao EY, Kramer JR, El-Serag H, et al. Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus. JAMA [Internet]. 2007;297(18):2010–7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17488966.

    CAS  Google Scholar 

  42. Carloni G, Fioretti D, Rinaldi M, Ponzetto A. Heterogeneity and coexistence of oncogenic mechanisms involved in HCV-associated B-cell lymphomas. Crit Rev Oncol Hematol [Internet]. 2019;138:156–71 Available from: http://www.ncbi.nlm.nih.gov/pubmed/31092372.

    Google Scholar 

  43. De Re V, De Vita S, Marzotto A, Gloghini A, Pivetta B, Gasparotto D, et al. Pre-malignant and malignant lymphoproliferations in an HCV-infected type II mixed cryoglobulinemic patient are sequential phases of an antigen-driven pathological process. Int J cancer [Internet]. 2000;87(2):211–6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10861476.

    Google Scholar 

  44. Zignego A-L, Giannini C, Ferri C. Hepatitis C virus-related lymphoproliferative disorders: an overview. World J Gastroenterol [Internet]. 2007;13(17):2467–78 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17552031.

    CAS  Google Scholar 

  45. Sansonno D, Tucci FA, Ghebrehiwet B, Lauletta G, Peerschke EIB, Conteduca V, et al. Role of the receptor for the globular domain of C1q protein in the pathogenesis of hepatitis C virus-related cryoglobulin vascular damage. J Immunol [Internet]. 2009;183(9):6013–20 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19828637.

    CAS  Google Scholar 

  46. •• El-Shamy A, Branch AD, Schiano TD, Gorevic PD. The Complement System and C1q in Chronic Hepatitis C Virus Infection and Mixed Cryoglobulinemia. Front Immunol [Internet]. 2018;9:1001 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29910796. An interesting review about the important role of C1q and gC1qR in mixed cryoglobulinemia related to HCV infection.

    Google Scholar 

  47. Roccatello D, Isidoro C, Mazzucco G, Mesiti A, Quattrocchio G, Amore A, et al. Role of monocytes in cryoglobulinemia-associated nephritis. Kidney Int [Internet]. 1993;43(5):1150–5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8510395.

    CAS  Google Scholar 

  48. Roccatello D, Morsica G, Picciotto G, Cesano G, Ropolo R, Bernardi MT, et al. Impaired hepatosplenic elimination of circulating cryoglobulins in patients with essential mixed cryoglobulinaemia and hepatitis C virus (HCV) infection. Clin Exp Immunol [Internet]. 1997;110(1):9–14 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9353142.

    CAS  Google Scholar 

  49. Sidana S, Rajkumar SV, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, et al. Clinical presentation and outcomes of patients with type 1 monoclonal cryoglobulinemia. Am J Hematol [Internet]. 2017;92(7):668–73 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28370486.

    CAS  Google Scholar 

  50. Terrier B, Karras A, Kahn J-E, Le Guenno G, Marie I, Benarous L, et al. The spectrum of type I cryoglobulinemia vasculitis: new insights based on 64 cases. Medicine (Baltimore) [Internet]. 2013;92(2):61–8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23429354.

    CAS  Google Scholar 

  51. De Vita S, Quartuccio L, Isola M, Mazzaro C, Scaini P, Lenzi M, et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum [Internet]. 2012;64(3):843–53 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22147661.

    Google Scholar 

  52. Zaltron S, Puoti M, Liberini P, Antonini L, Quinzanini M, Manni M, et al. High prevalence of peripheral neuropathy in hepatitis C virus infected patients with symptomatic and asymptomatic cryoglobulinaemia. Ital J Gastroenterol Hepatol [Internet]. 1998;30(4):391–5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9789135.

    CAS  Google Scholar 

  53. Ciompi ML, Marini D, Siciliano G, Melchiorre D, Bazzichi L, Sartucci F, et al. Cryoglobulinemic peripheral neuropathy: neurophysiologic evaluation in twenty-two patients. Biomed Pharmacother [Internet]. 1996;50(8):329–36 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8952851.

    CAS  Google Scholar 

  54. Gemignani F, Brindani F, Alfieri S, Giuberti T, Allegri I, Ferrari C, et al. Clinical spectrum of cryoglobulinaemic neuropathy. J Neurol Neurosurg Psychiatry. 2005;76(10):1410–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Collins MP. The vasculitic neuropathies. Curr Opin Neurol. 2012;25(5):573–85.

    CAS  PubMed  Google Scholar 

  56. Shihabi ZK. Cryoglobulins: An important but neglected clinical test. Ann Clin Lab Sci. 2006;36:395–408.

  57. Saadoun D, Terrier B, Semoun O, Sene D, Maisonobe T, Musset L, et al. Hepatitis C virus associated polyarteritis nodosa. Arthritis Care Res. 2011;63(3):427–35.

    CAS  Google Scholar 

  58. Terrier B, Carrat F, Krastinova E, Marie I, Launay D, Lacraz A, 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 [Internet]. 2013;72(3):374–80 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22586172.

    Google Scholar 

  59. P.D. G, H.J. K, Y. L, R. K, M. M, P. P, et al. Mixed cryoglobulinemia: Clinical aspects and long-term follow-up of 40 patients. Am J Med 1980;69(2):287–308.

  60. Tarantino A, Campise M, Banfi G, Confalonieri R, Bucci A, Montoli A, et al. Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int. 1995;47(2):618–23.

    CAS  PubMed  Google Scholar 

  61. Roccatello D, Fornasieri A, Giachino O, Rossi D, Beltrame A, Banfi G, et al. Multicenter study on hepatitis C virus-related cryoglobulinemic glomerulonephritis. Am J Kidney Dis [Internet]. 2007;49(1):69–82 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17185147.

    CAS  Google Scholar 

  62. Beddhu S, Bastacky S, Johnson JP. The clinical and morphologic spectrum of renal cryoglobulinemia. Medicine (Baltimore) [Internet]. 2002;81(5):398–409 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12352634.

    CAS  Google Scholar 

  63. Coliche V, Sarda M-N, Laville M, Chapurlat R, Rheims S, Sève P, et al. Predictive factors of renal involvement in cryoglobulinaemia: a retrospective study of 153 patients. Clin Kidney J [Internet]. 2018;12(3):365–72 Available from: https://academic.oup.com/ckj/article/12/3/365/5168442.

    Google Scholar 

  64. Terrier B, Saadoun D, Sène D, Scerra S, Musset L, Cacoub P. Presentation and outcome of gastrointestinal involvement in hepatitis C virus-related systemic vasculitis: a case-control study from a single-centre cohort of 163 patients. Gut [Internet]. 2010;59(12):1709–15 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20841367.

    Google Scholar 

  65. Della Rossa A, Tavoni A, D’Ascanio A, Catarsi E, Marchi F, Bencivelli W, et al. Mortality rate and outcome factors in mixed cryoglobulinaemia: the impact of hepatitis C virus. Scand J Rheumatol [Internet]. 2010;39(2):167–70 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20337547.

    Google Scholar 

  66. Antonelli A, Ferri C, Fallahi P, Giuggioli D, Nesti C, Longombardo G, et al. Thyroid involvement in patients with overt HCV-related mixed cryoglobulinaemia. QJM [Internet]. 2004;97(8):499–506 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15256607.

    CAS  Google Scholar 

  67. Antonelli A, Ferri C, Fallahi P, Sebastiani M, Nesti C, Barani L, et al. Type 2 diabetes in hepatitis C-related mixed cryoglobulinaemia patients. Rheumatology (Oxford) [Internet]. 2004;43(2):238–40 Available from: http://www.ncbi.nlm.nih.gov/pubmed/13130149.

    CAS  Google Scholar 

  68. Ferri C, Bertozzi MA, Zignego AL. Erectile dysfunction and hepatitis C virus infection. JAMA [Internet]. 2002;288(6):698–9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12169072.

    Google Scholar 

  69. Retamozo S, Díaz-Lagares C, Bosch X, Bové A, Brito-Zerón P, Gómez M-E, et al. Life-Threatening Cryoglobulinemic Patients With Hepatitis C: Clinical Description and Outcome of 279 Patients. Medicine (Baltimore) [Internet]. 2013;92(5):273–84 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23974248.

    Google Scholar 

  70. Ali MA, Kayani WZ, Linzie BM, Punjabi G V, Wetmore JB. Myopericarditis in a patient with hepatitis C and cryoglobulinemic renal disease. Clin Case Reports [Internet]. 2017;5(5):616–620. Available from: https://doi.org/10.1002/ccr3.788

    PubMed  PubMed Central  Google Scholar 

  71. Ramos-Casals M, Robles A, Brito-Zerón P, Nardi N, Nicolás JM, Forns X, et al. Life-threatening Cryoglobulinemia: Clinical and immunological characterization of 29 cases. Semin Arthritis Rheum. 2006;36:189–96.

    PubMed  Google Scholar 

  72. Damoiseaux J, Cohen Tervaert JW. Diagnostics and Treatment of Cryoglobulinaemia: It Takes Two to Tango. Clin Rev Allerg Immu. 2014;47:299–310.

    Google Scholar 

  73. Sargur R, Egner W. Appropriate cryoglobulin investigations - The author responds. Ann Clin Biochem. 2010;47:491–2.

    Google Scholar 

  74. Leblond V, Kastritis E, Advani R, Ansell SM, Buske C, Castillo JJ, et al. Treatment recommendations from the eighth international workshop on Waldenström’s Macroglobulinemia. Blood [Internet]. 2016;128(10):1321–8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27432877.

    CAS  PubMed  Google Scholar 

  75. Mazzucchelli M, Frustaci AM, Deodato M, Cairoli R, Tedeschi A. Waldenstrom’s Macroglobulinemia: an update. Mediterr J Hematol infect Dis [Internet]. 2018;10(1):e2018004 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29326801.

    Google Scholar 

  76. Simmons B, Saleem J, Hill A, Riley RD, Cooke GS. Risk of Late Relapse or Reinfection With Hepatitis C Virus After Achieving a Sustained Virological Response: A Systematic Review and Meta-analysis. Clin Infect Dis [Internet]. 2016;62(6):683–94 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26787172.

    Google Scholar 

  77. Banerjee D, Reddy KR. Review article: safety and tolerability of direct-acting anti-viral agents in the new era of hepatitis C therapy. Aliment Pharmacol Ther [Internet]. 2016;43(6):674–96 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26787287.

    CAS  Google Scholar 

  78. •• Cacoub P, Si Ahmed SN, Ferfar Y, Pol S, Thabut D, Hezode C, et al. Long-term Efficacy of Interferon-Free Antiviral Treatment Regimens in Patients With Hepatitis C Virus-Associated Cryoglobulinemia Vasculitis. Clin Gastroenterol Hepatol [Internet]. 2019;17(3):518–26 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29857143. A recent international and prospective study that confirmed the effectiveness and good tolerance of direct - acting antiviral agents in HCV related cryoglobulinemic vasculitis.

    CAS  Google Scholar 

  79. 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 [Internet]. 2012;64(3):835–42 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22147444.

    CAS  Google Scholar 

  80. • Galli M, Monti G, Marson P, Scaini P, Pietrogrande M, Candela M, et al. Recommendations for managing the manifestations of severe and life-threatening mixed cryoglobulinemia syndrome. Autoimmun rev [Internet]. 2019 Jun; available from: https://linkinghub.elsevier.com/retrieve/pii/S1568997219301351. An evidence based guideline made by an italian consensus panel for treatment of severe and life threatening manifestations of mixed cryoglobulinemias.

  81. Dammacco F, Tucci FA, Lauletta G, Gatti P, De Re V, Conteduca V, et al. Pegylated interferon-α, ribavirin, and rituximab combined therapy of hepatitis C virus-related mixed cryoglobulinemia: A long-term study. Blood. 2010;116:343–53.

    CAS  PubMed  Google Scholar 

  82. Visentini M, Tinelli C, Colantuono S, Monti M, Ludovisi S, Gragnani L, et al. Efficacy of low-dose rituximab for the treatment of mixed cryoglobulinemia vasculitis: phase II clinical trial and systematic review. Autoimmun Rev [Internet]. 2015;14(10):889–96 Available from: https://linkinghub.elsevier.com/retrieve/pii/S1568997215001214.

    CAS  Google Scholar 

  83. Colantuono S, Mitrevski M, Yang B, Tola J, Carlesimo M, De Sanctis GM, et al. Efficacy and safety of long-term treatment with low-dose rituximab for relapsing mixed cryoglobulinemia vasculitis. Clin Rheumatol [Internet]. 2017;36(3):617–23 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28111716.

    Google Scholar 

  84. Stefanutti C, Vivenzio A, Di Giacomo S, Labbadia G, Mazza F, D’Alessandri G, et al. Immunoadsorption apheresis and immunosuppressive drug therapy in the treatment of complicated HCV-related cryoglobulinemia. J Clin Apher [Internet]. 2009;24(6):241–6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19927363.

    Google Scholar 

  85. • Marson P, Monti G, Montani F, Riva A, Mascia MT, Castelnovo L, et al. Apheresis treatment of cryoglobulinemic vasculitis: A multicentre cohort study of 159 patients. Transfus Apher Sci [Internet]. 2018;57(5):639–45 Available from: http://www.ncbi.nlm.nih.gov/pubmed/30228046. An italian retrospective study of 159 patients that suggests the use of apheresis treatment in early life threatening cryoglobulinemic vasculitis.

    CAS  Google Scholar 

  86. Puisset F, White-Koning M, Kamar N, Huart A, Haberer F, Blasco H, et al. Population pharmacokinetics of rituximab with or without plasmapheresis in kidney patients with antibody-mediated disease. Br J Clin Pharmacol [Internet]. 2013;76(5):734–40 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23432476.

    CAS  Google Scholar 

  87. Terrier B, Marie I, Lacraz A, Belenotti P, Bonnet F, Chiche L, et al. Non HCV-related infectious cryoglobulinemia vasculitis: Results from the French nationwide CryoVas survey and systematic review of the literature. J Autoimmun [Internet]. 2015;65:74–81 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26320984.

    Google Scholar 

  88. Hanbali A, Khaled Y. Incidence of hepatitis B reactivation following Rituximab therapy. Am J Hematol [Internet]. 2009;84(3):195 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19140189.

    Google Scholar 

  89. Yeo W, Chan TC, Leung NWY, Lam WY, Mo FKF, Chu MT, et al. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol [Internet]. 2009;27(4):605–11 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19075267.

    CAS  Google Scholar 

  90. Khan ZH, Ilyas K, Ghazanfar H, Khan HH, Hussain Q, Hammad S, et al. Fatal Fulminant Hepatitis from Rituximab-induced Hepatitis B Reactivation in a Patient with Follicular Lymphoma: A Case Report and a Brief Review of Literature. Cureus [Internet]. 2018;10(3):e2257 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29725560.

    Google Scholar 

  91. Terrier B, Krastinova E, Marie I, Launay D, Lacraz A, Belenotti P, et al. Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey. Blood [Internet]. 2012;119(25):5996–6004 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22474249.

    CAS  Google Scholar 

  92. Schwartz J, Padmanabhan A, Aqui N, Balogun RA, Connelly-Smith L, Delaney M, et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice-Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Seventh Special Issue. J Clin Apher [Internet]. 2016;31(3):149–62 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27322218.

    Google Scholar 

  93. Terrier B, Semoun O, Saadoun D, Sène D, Resche-Rigon M, Cacoub P. Prognostic factors in patients with hepatitis C virus infection and systemic vasculitis. Arthritis Rheum [Internet]. 2011;63(6):1748–57 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21400476.

    Google Scholar 

  94. Landau D-A, Scerra S, Sene D, Resche-Rigon M, Saadoun D, Cacoub P. Causes and predictive factors of mortality in a cohort of patients with hepatitis C virus-related cryoglobulinemic vasculitis treated with antiviral therapy. J Rheumatol [Internet]. 2010;37(3):615–21 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20110523.

    CAS  Google Scholar 

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Fuentes, A., Mardones, C. & Burgos, P.I. Understanding the Cryoglobulinemias. Curr Rheumatol Rep 21, 60 (2019). https://doi.org/10.1007/s11926-019-0859-0

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