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Clinical practice: hepatitis C virus infection, cryoglobulinemia and cryoglobulinemic vasculitis

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Abstract

Cryoglobulins are circulating immunoglobulins that reversibly precipitate at temperatures below 37 °C. Type-II cryoglobulins consist of monoclonal IgM/polyclonal IgG immune complexes (ICs), whereas in type-III cryoglobulins both IgM and IgG are polyclonal. The clinical condition resulting from the presence of cryoglobulins in the blood is called mixed cryoglobulinemia (MC), which can be asymptomatic or manifest as cryoglobulinemic vasculitis (CV). Type-I cryoglobulins, consisting of a single monoclonal isotype, are detected in patients with lymphoproliferative disorders. It is now established that > 90% of MCs are associated with HCV infection. Clinically, the spectrum of symptoms may range in severity from occasional purpuric eruptions to life-threatening features. In addition to the development of liver cirrhosis and hepatocellular carcinoma, the possible progression of HCV-positive CV patients to B-cell non-Hodgkin lymphoma (B-NHL) has been reported. The pathogenetic role played by HCV infection in the onset of B-NHL is suggested by regression of the latter following the achievement of a sustained virologic response (SVR). For several years, interferon-α alone or combined with ribavirin has been the standard of care. However, the rates of clinical, biochemical, and virologic responses have been low, and the occurrence of relapse frequent. The addition of rituximab has resulted in a higher rate of responses. With the advent of direct-acting antiviral agents, SVR has been achieved in ~ 95% of CV patients. However, in a minority of patients, despite SVR, CV may persist or reappear over variable lengths of time from the completion of therapy. The eventual appearance of B-NHL is also possible.

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Abbreviations

BAFF:

B-cell activating factor

CV:

Cryoglobulinemic vasculitis

DAAs:

Direct-acting antiviral agents

DLBCL:

Diffuse large B-cell lymphoma

EMC:

Essential mixed cryoglobulinemia

GCs:

Glucocorticoids

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

ICs:

Immune complexes

IFN-α:

Interferon-α

MC:

Mixed cryoglobulins or mixed cryoglobulinemia

MoAb:

Monoclonal antibody

MZL:

Marginal zone lymphoma

NHL:

Non-Hodgkin’s lymphoma

NVC:

Nailfold videocapillaroscopy

pIFN-α:

Pegylated interferon-α

RBV:

Ribavirin

RF:

Rheumatoid factor

RTX:

Rituximab

SVR:

Sustained virologic response

References

  1. Wintrobe MM, Buell MV. Hyperproteinemia associated with multiple myeloma. Bull Johns Hopkins Hosp. 1933;52:156–65.

    Google Scholar 

  2. Lerner AB, Watson CJ. Studies of cryoglobulins. I. Unusual purpura associated with the presence of a high concentration of cryoglobulin (cold precipitable serum globulin). Am J Med Sci. 1947;214:410–5.

    Article  CAS  PubMed  Google Scholar 

  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;32:142–7.

    Article  CAS  PubMed  Google Scholar 

  4. Meltzer M, Franklin EC. Cryoglobulinemia—a study of twenty-nine patients. I. IgG and IgM cryoglobulins and factors affecting cryoprecipitability. Am J Med. 1966;40:828–36.

    Article  CAS  PubMed  Google Scholar 

  5. 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;57:775–88.

    Article  CAS  PubMed  Google Scholar 

  6. Bonomo L, Casato M, Afeltra A, Caccavo D. Treatment of idiopathic mixed cryoglobulinemia with alpha interferon. Am J Med. 1987;83(4):726–30.

    Article  CAS  PubMed  Google Scholar 

  7. Pascual M, Perrin L, Giostra E, Schifferli JA. Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis. 1990;162:569–70.

    Article  CAS  PubMed  Google Scholar 

  8. Gorevic PD, Frangione B. Mixed cryoglobulinemia cross-reactive idiotypes (CRI): implications for the relationship of MC to rheumatic and lymphoproliferative diseases. Semin Hematol. 1991;28:79–94.

    CAS  PubMed  Google Scholar 

  9. Ferri C, Monti M, La Civita L, Careccia G, Mazzaro C, Longombardo G, et al. Hepatitis C virus infection in non-Hodgkin’s B-cell lymphoma complicating mixed cryoglobulinemia. Eur J Clin Invest. 1994;24:781–4.

    Article  CAS  PubMed  Google Scholar 

  10. Hermine O, Lefrère F, Bronowicki JP, Mariette X, Jondeau K, Eclache-Saudreau V, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med. 2002;347:89–94.

    Article  CAS  PubMed  Google Scholar 

  11. Sansonno D, De Re V, Lauletta G, Tucci FA, Boiocchi M, Dammacco F. Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-CD20. Blood. 2003;101:3818–26.

    Article  CAS  PubMed  Google Scholar 

  12. Levine JW, Gota C, Fessler BJ, Calabrese LH, Cooper SM. Persistent cryoglobulinemic vasculitis following successful treatment of hepatitis C virus. J Rheumatol. 2005;32:1164–7.

    PubMed  Google Scholar 

  13. Sise ME, Bloom AK, Wisocky J, Lin MV, Gustafson JL, Lundquist AL, et al. Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents. Hepatology. 2016;63:408–17.

    Article  CAS  PubMed  Google Scholar 

  14. Abel G, Zhang QX, Agnello V. Hepatitis C virus infection in type II mixed cryoglobulinemia. Arthritis Rheum. 1993;36:1341–9.

    Article  CAS  PubMed  Google Scholar 

  15. Dammacco F, Racanelli V, Russi S, Sansonno D. The expanding spectrum of HCV-related cryoglobulinemic vasculitis: a narrative review. Clin Exp Med. 2016;16:233–42.

    Article  CAS  PubMed  Google Scholar 

  16. 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). 2013;92:245–56.

    Article  CAS  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med. 1992;327:1490–5.

    Article  CAS  PubMed  Google Scholar 

  19. Dammacco F, Sansonno D. Antibodies to hepatitis C virus in essential mixed cryoglobulinaemia. Clin Exp Immunol. 1992;87:352–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Misiani R, Bellavita P, Fenili D, Borelli G, Marchesi D, Massazza M, et al. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med. 1992;117:573–7.

    Article  CAS  PubMed  Google Scholar 

  21. Dammacco F, Sansonno D, Cornacchiulo V, Mennuni C, Carbone R, Lauletta G, et al. Hepatitis C virus infection and mixed cryoglobulinemia: a striking association. Int J Clin Lab Res. 1993;23:45–9.

    Article  CAS  PubMed  Google Scholar 

  22. Cacoub P, Fabiani FL, Musset L, Perrin M, Frangeul L, Leger JM, et al. Mixed cryoglobulinemia and hepatitis C virus. Am J Med. 1994;96:124–32.

    Article  CAS  PubMed  Google Scholar 

  23. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65:1–11.

    Article  CAS  PubMed  Google Scholar 

  24. Dammacco F, Sansonno D. Therapy for hepatitis C virus-related cryoglobulinemic vasculitis. N Engl J Med. 2013;369:1035–45.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. Mascia MT, Ferrari D, Campioli D, Sandri G, Mussini C, Ferri C. Non HCV-related mixed cryoglobulinemia. Dig Liver Dis. 2007;39(Suppl 1):S61–4.

    Article  PubMed  Google Scholar 

  27. 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. 2015;65:74–81.

    Article  PubMed  Google Scholar 

  28. Galli M, Oreni L, Saccardo F, et al. HCV-unrelated cryoglobulinaemic vasculitis: the results of a prospective observational study by the Italian Group for the Study of Cryoglobulinaemias (GISC). Clin Exp Rheumatol. 2017;35(Suppl 103):67–76.

    PubMed  Google Scholar 

  29. Kosmas N, Kontos A, Panayiotakopoulos G, Dimitrakopoulos A, Kordossis T. Decreased prevalence of mixed cryoglobulinemia in the HAART era among HIV-positive, HCV-negative patients. J Med Virol. 2006;78:1257–61.

    Article  PubMed  Google Scholar 

  30. Mazzaro C, Dal Maso L, Urraro T, Mauro E, Castelnovo L, Casarin P, et al. Hepatitis B virus related cryoglobulinemic vasculitis: a multicentre open label study from the Gruppo Italiano di Studio delle Crioglobulinemie—GISC. Dig Liver Dis. 2016;48:780–4.

    Article  PubMed  Google Scholar 

  31. Bazerbachi F, Leise MD, Watt KD, Murad MH, Prokop LJ, Haffar S. Systematic review of mixed cryoglobulinemia associated with hepatitis E virus infection: association or causation? Gastroenterol Rep (Oxf). 2017;5:178–84.

    Article  Google Scholar 

  32. Monti G, Saccardo F, Castelnovo L, Novati P, Sollima S, Riva A, et al. Prevalence of mixed cryoglobulinaemia syndrome and circulating cryoglobulins in a population-based survey: the Origgio study. Autoimmun Rev. 2014;13:609–14.

    Article  CAS  PubMed  Google Scholar 

  33. Meeting of the International Task Force for Disease Eradication, June 2017. Wkly Epidemiol Rec. 2017;92:537–56.

  34. Agnello V. The etiology and pathophysiology of mixed cryoglobulinemia secondary to hepatitis C virus infection. Springer Semin Immunopathol. 1997;19:111–29.

    Article  CAS  PubMed  Google Scholar 

  35. Lamprecht P, Gause A, Gross WL. Cryoglobulinemic vasculitis. Arthritis Rheum. 1999;42:2507–16.

    Article  CAS  PubMed  Google Scholar 

  36. Ferri C, Mascia MT. Cryoglobulinemic vasculitis. Curr Opin Rheumatol. 2006;18:54–63.

    PubMed  Google Scholar 

  37. Sansonno D, Carbone A, De Re V, Dammacco F. Hepatitis C virus infection, cryoglobulinaemia, and beyond. Rheumatology (Oxford). 2007;46:572–8.

    Article  CAS  Google Scholar 

  38. Cacoub P, Saadoun D. Hepatitis C virus infection induced vasculitis. Clin Rev Allergy Immunol. 2008;35:30–9.

    Article  CAS  PubMed  Google Scholar 

  39. Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet. 2012;379:348–60.

    Article  CAS  PubMed  Google Scholar 

  40. Fabris M, Quartuccio L, Sacco S, De Marchi G, Pozzato G, Mazzaro C, Ferraccioli G, Migone TS, De Vita S. B-Lymphocyte stimulator (BLyS) up-regulation in mixed cryoglobulinaemia syndrome and hepatitis-C virus infection. Rheumatology (Oxford). 2007;46:37–43.

    Article  CAS  Google Scholar 

  41. 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. 2012;170:231–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sansonno D, De Vita S, Iacobelli AR, Cornacchiulo V, Boiocchi M, Dammacco F. Clonal analysis of intrahepatic B cells from HCV-infected patients with and without mixed cryoglobulinemia. J Immunol. 1998;160:3594–601.

    CAS  PubMed  Google Scholar 

  43. 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. 2000;43:94–102.

    Article  PubMed  Google Scholar 

  44. Sansonno D, Dammacco F. Hepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations. Lancet Infect Dis. 2005;5:227–36.

    Article  PubMed  Google Scholar 

  45. Cutolo M, Pizzorni C, Secchi ME, Sulli A. Capillaroscopy. Best Pract Res Clin Rheumatol. 2008;22:1093–108.

    Article  PubMed  Google Scholar 

  46. 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. 2007;49:69–82.

    Article  CAS  PubMed  Google Scholar 

  47. Casato M, Saadoun D, Marchetti A, Limal N, Picq C, Pantano P, et al. Central nervous system involvement in hepatitis C virus cryoglobulinemia vasculitis: a multicenter case-control study using magnetic resonance imaging and neuropsychological tests. J Rheumatol. 2005;32:484–8.

    PubMed  Google Scholar 

  48. Monaco S, Mariotto S, Ferrari S, Calabrese M, Zanusso G, Gajofatto A, Sansonno D, Dammacco F. Hepatitis C virus-associated neurocognitive and neuropsychiatric disorders: advances in 2015. World J Gastroenterol. 2015;21:11974–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zackrison LH, Katz P. Bronchiolitis obliterans organizing pneumonia associated with essential mixed cryoglobulinemia. Arthritis Rheum. 1993;36:1627–30.

    Article  CAS  PubMed  Google Scholar 

  50. 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. 2010;59:1709–15.

    Article  PubMed  Google Scholar 

  51. Culclasure TF, Dorogy ME, Enzenauer RJ. Cryoglobulinemia: a reversible cause of dilated cardiomyopathy. Am Heart J. 1996;131:1044–6.

    Article  CAS  PubMed  Google Scholar 

  52. Karras A, Potier L, Reboux AH, Coldea N, Perdrix L, Jacquot C, et al. Cryoglobulin-induced cardiomyopathy. J Am Coll Cardiol. 2010;55:e13.

    Article  PubMed  Google Scholar 

  53. Terrier B, Karras A, Cluzel P, Collet JP, Sène D, Saadoun D, et al. Presentation and prognosis of cardiac involvement in hepatitis C virus-related vasculitis. Am J Cardiol. 2013;111:265–72.

    Article  PubMed  Google Scholar 

  54. Sebastiani M, Giuggioli D, Colaci M, Fallahi P, Gragnani L, Antonelli A, et al. HCV-related rheumatic manifestations and therapeutic strategies. Curr Drug Targets. 2017;18:803–10.

    Article  CAS  PubMed  Google Scholar 

  55. Lormeau C, Falgarone G, Roulot D, Boissier MC. Rheumatologic manifestations of chronic hepatitis C infection. Joint Bone Spine. 2006;73:633–8.

    Article  PubMed  Google Scholar 

  56. Ferri C, Sebastiani M, Antonelli A, Colaci M, Manfredi A, Giuggioli D. Current treatment of hepatitis C-associated rheumatic diseases. Arthritis Res Ther. 2012;14:215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Fiore CE, Riccobene S, Mangiafico R, Santoro F, Pennisi P. Hepatitis C-associated osteosclerosis (HCAO): report of a new case with involvement of the OPG/RANKL system. Osteoporos Int. 2005;16:2180–4.

    Article  CAS  PubMed  Google Scholar 

  58. Manganelli P, Giuliani N, Fietta P, Mancini C, Lazzaretti M, Pollini A, et al. OPG/RANKL system imbalance in a case of hepatitis C-associated osteosclerosis: the pathogenetic key? Clin Rheumatol. 2005;24:296–300.

    Article  PubMed  Google Scholar 

  59. Della Rossa A, Tavoni A, Bombardieri S. Hyperviscosity syndrome in cryoglobulinemia: clinical aspects and therapeutic considerations. Semin Thromb Hemost. 2003;29:473–7.

    Article  PubMed  Google Scholar 

  60. Stone MJ, Bogen SA. Evidence-based focused review of management of hyperviscosity syndrome. Blood. 2012;119:2205–8.

    Article  CAS  PubMed  Google Scholar 

  61. Antonelli A, Ferri C, Ferrari SM, Colaci M, Fallahi P. Immunopathogenesis of HCV-related endocrine manifestations in chronic hepatitis and mixed cryoglobulinemia. Autoimmun Rev. 2008;8:18–23.

    Article  CAS  PubMed  Google Scholar 

  62. Ferri C, Colaci M, Fallahi P, Ferrari SM, Antonelli A, Giuggioli D. Thyroid involvement in hepatitis C virus-infected patients with/without mixed cryoglobulinemia. Front Endocrinol (Lausanne). 2017;8:159.

    Article  Google Scholar 

  63. 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.

    Article  PubMed  Google Scholar 

  64. Landau DA, 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. 2010;37:615–21.

    Article  CAS  PubMed  Google Scholar 

  65. Cacoub P, Vautier M, Desbois AC, Lafuma A, Saadoun D. Effectiveness and cost of hepatitis C virus cryoglobulinaemia vasculitis treatment: from interferon-based to direct-acting antivirals era. Liver Int. 2017;37:1805–13.

    Article  CAS  PubMed  Google Scholar 

  66. Gisbert JP, García-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in B-cell non-Hodgkin’s lymphoma: systematic review and meta-analysis. Gastroenterology. 2003;125:1723–32.

    Article  PubMed  Google Scholar 

  67. 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. 2005;165:101–5.

    Article  PubMed  Google Scholar 

  68. de Sanjose S, Benavente Y, Vajdic CM, Engels EA, Morton LM, Bracci PM, et al. Hepatitis C and non-Hodgkin lymphoma among 4784 cases and 6269 controls from the International Lymphoma Epidemiology Consortium. Clin Gastroenterol Hepatol. 2008;6:451–8.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Zignego AL, Gragnani L, Piluso A, Sebastiani M, Giuggioli D, Fallahi P, et al. Virus-driven autoimmunity and lymphoproliferation: the example of HCV infection. Expert Rev Clin Immunol. 2015;11:15–31.

    Article  CAS  PubMed  Google Scholar 

  70. Iqbal T, Mahale P, Turturro F, Kyvernitakis A, Torres HA. Prevalence and association of hepatitis C virus infection with different types of lymphoma. Int J Cancer. 2016;138:1035–7.

    Article  CAS  PubMed  Google Scholar 

  71. Couronné L, Bachy E, Roulland S, Nadel B, Davi F, Armand M, et al. From hepatitis C virus infection to B-cell lymphoma. Ann Oncol. 2018;29:92–100.

    Article  PubMed  Google Scholar 

  72. Sansonno D, De Vita S, Cornacchiulo V, Carbone A, Boiocchi M, Dammacco F. Detection and distribution of hepatitis C virus-related proteins in lymph nodes of patients with type II mixed cryoglobulinemia and neoplastic or non-neoplastic lymphoproliferation. Blood. 1996;88:4638–45.

    CAS  PubMed  Google Scholar 

  73. Merli M, Visco C, Spina M, Luminari S, Ferretti VV, Gotti M, et al. Outcome prediction of diffuse large B-cell lymphomas associated with hepatitis C virus infection: a study on behalf of the Fondazione Italiana Linfomi. Haematologica. 2014;99:489–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Peveling-Oberhag J, Arcaini L, Bankov K, Zeuzem S, Herrmann E. The anti-lymphoma activity of antiviral therapy in HCV-associated B-cell non-Hodgkin lymphomas: a meta-analysis. J Viral Hepat. 2016;23:536–44.

    Article  CAS  PubMed  Google Scholar 

  75. Dal Maso L, Franceschi S. Hepatitis C virus and risk of lymphoma and other lymphoid neoplasms: a meta-analysis of epidemiologic studies. Cancer Epidemiol Biomarkers Prev. 2006;15:2078–85.

    Article  Google Scholar 

  76. Mele A, Pulsoni A, Bianco E, Musto P, Szklo A, Sanpaolo MG, et al. Hepatitis C virus and B-cell non-Hodgkin lymphomas: an Italian multicenter case-control study. Blood. 2003;102:996–9.

    Article  CAS  PubMed  Google Scholar 

  77. Paydas S. Hepatitis C virus and lymphoma. Crit Rev Oncol Hematol. 2015;93:246–56.

    Article  PubMed  Google Scholar 

  78. Besson C, Canioni D, Lepage E, Pol S, Morel P, Lederlin P, Groupe d’Etude des Lymphomes de l’Adulte Programs, et al. Characteristics and outcome of diffuse large B-cell lymphoma in hepatitis C virus-positive patients in LNH 93 and LNH 98 Groupe d’Etude des Lymphomes de l’Adulte programs. J Clin Oncol. 2006;24:953–60.

    Article  PubMed  Google Scholar 

  79. Arcaini L, Besson C, Frigeni M, Fontaine H, Goldaniga M, Casato M, et al. Interferon-free antiviral treatment in B-cell lymphoproliferative disorders associated with hepatitis C virus infection. Blood. 2016;128:2527–32.

    Article  CAS  PubMed  Google Scholar 

  80. Kawamura Y, Ikeda K, Arase Y, Yatsuji H, Sezaki H, Hosaka T, et al. Viral elimination reduces incidence of malignant lymphoma in patients with hepatitis C. Am J Med. 2007;120:1034–41.

    Article  CAS  PubMed  Google Scholar 

  81. Peveling-Oberhag J, Arcaini L, Hansmann ML, Zeuzem S. Hepatitis C-associated B-cell non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical management. J Hepatol. 2013;59:169–77.

    Article  CAS  PubMed  Google Scholar 

  82. Lerat H, Berby F, Trabaud MA, Vidalin O, Major M, Trepo C, et al. Specific detection of hepatitis C virus minus strand RNA in hematopoietic cells. J Clin Invest. 1996;97:845–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lanford RE, Chavez D, Chisari FV, Sureau C. Lack of detection of negative strand hepatitis C virus RNA in peripheral blood mononuclear cells and other extrahepatic tissues by the highly strand-specific rTth reverse transcriptase PCR. J Virol. 1995;69:8079–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 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. 2010;135:459–65.

    Article  CAS  PubMed  Google Scholar 

  85. Sansonno D, Lotesoriere C, Cornacchiulo V, Fanelli M, Gatti P, Iodice G, et al. Hepatitis C virus infection involves CD34(+) hematopoietic progenitor cells in hepatitis C virus chronic carriers. Blood. 1998;92:3328–37.

    CAS  PubMed  Google Scholar 

  86. Machida K, Cheng KT, Sung VM, Shimodaira S, Lindsay KL, Levine AM, et al. Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes. Proc Natl Acad Sci U S A. 2004;101:4262–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tucci FA, Broering R, Johansson P, Schlaak JF, Kuppers R. B cells in chronically hepatitis C virus-infected individuals lack a virus-induced mutation signature in the TP53, CTNNB1, and BCL6 genes. J Virol. 2013;87:2956–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Casato M, Laganà B, Antonelli G, Dianzani F, Bonomo L. Long-term results of therapy with interferon-alpha for type II essential mixed cryoglobulinemia. Blood. 1991;78:3142–7.

    CAS  PubMed  Google Scholar 

  89. Ferri C, Marzo E, Longombardo G, Lombardini F, La Civita L, Vanacore R, et al. Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial. Blood. 1993;81:1132–6.

    CAS  PubMed  Google Scholar 

  90. Dammacco F, Sansonno D, Han JH, Shyamala V, Cornacchiulo V, Iacobelli AR, 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;84:3336–43.

    CAS  PubMed  Google Scholar 

  91. Misiani R, Bellavita P, Fenili D, Vicari O, Marchesi D, Sironi PL, et al. Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med. 1994;330:751–6.

    Article  CAS  PubMed  Google Scholar 

  92. Asselah T, Estrabaud E, Bieche I, Lapalus M, De Muynck S, Vidaud M, et al. Hepatitis C: viral and host factors associated with non-response to pegylated interferon plus ribavirin. Liver Int. 2010;30:1259–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Vallat L, Benhamou Y, Gutierrez M, Ghillani P, Hercher C, Thibault V, et al. Clonal B cell populations in the blood and liver of patients with chronic hepatitis C virus infection. Arthritis Rheum. 2004;50:3668–78.

    Article  PubMed  Google Scholar 

  94. Charles ED, Brunetti C, Marukian S, Ritola KD, Talal AH, Marks K, et al. Clonal B cells in patients with hepatitis C virus-associated mixed cryoglobulinemia contain an expanded anergic CD21low B-cell subset. Blood. 2011;117:5425–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zaja F, De Vita S, Mazzaro C, Sacco S, Damiani D, De Marchi G, et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood. 2003;101:3827–34.

    Article  CAS  PubMed  Google Scholar 

  96. Ferri C, Cacoub P, Mazzaro C, Roccatello D, Scaini P, Sebastiani M, et al. Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: results of multicenter cohort study and review of the literature. Autoimmun Rev. 2011;11:48–55.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  98. Saadoun D, Resche Rigon M, Sene D, Terrier B, Karras A, Perard L, et al. Rituximab plus Peg-interferon-alpha/ribavirin compared with Peg-interferon-alpha/ribavirin in hepatitis C-related mixed cryoglobulinemia. Blood. 2010;116:326–34.

    Article  CAS  PubMed  Google Scholar 

  99. 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;64:835–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Saadoun D, Resche Rigon M, Pol S, Thibault V, Blanc F, Pialoux G, et al. PegIFNα/ribavirin/protease inhibitor combination in severe hepatitis C virus-associated mixed cryoglobulinemia vasculitis. J Hepatol. 2015;62:24–30.

    Article  CAS  PubMed  Google Scholar 

  101. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2016. J Hepatol. 2017;66:153–94.

    Article  Google Scholar 

  102. American Association for the Study of Liver Disease, Infectious Diseases Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. 2017 (http://www.hcvguidelines.org).

  103. van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308:2584–93.

    Article  PubMed  Google Scholar 

  104. Zignego AL, Ramos-Casals M, Ferri C, Saadoun D, Arcaini L, Roccatello D, ISG-EHCV, et al. International therapeutic guidelines for patients with HCV-related extrahepatic disorders. A multidisciplinary expert statement. Autoimmun Rev. 2017;16:523–41.

    Article  PubMed  Google Scholar 

  105. Ramos-Casals M, Zignego AL, Ferri C, Brito-Zerón P, Retamozo S, Casato M, International Study Group of Extrahepatic Manifestations related to HCV (ISG-EHCV), et al. Evidence-based recommendations on the management of extrahepatic manifestations of chronic hepatitis C virus infection. J Hepatol. 2017;66:1282–99.

    Article  PubMed  Google Scholar 

  106. Visentini M, Ludovisi S, Petrarca A, Pulvirenti F, Zaramella M, Monti M, 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;10:714–9.

    Article  CAS  PubMed  Google Scholar 

  107. Rockx MA, Clark WF. Plasma exchange for treating cryoglobulinemia: a descriptive analysis. Transfus Apher Sci. 2010;42:247–51.

    Article  CAS  PubMed  Google Scholar 

  108. Olson N, Yerrabothala S, Dunbar N. Successful use of cryocrit for monitoring response to therapeutic plasma exchange in type 1 cryoglobulinemia. J Clin Apher. 2016;31:403–4.

    Article  PubMed  Google Scholar 

  109. Reig M, Mariño Z, Perelló C, Iñarrairaegui M, Ribeiro A, Lens S, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol. 2016;65:719–26.

    Article  CAS  PubMed  Google Scholar 

  110. Grandhe S, Frenette CT. Occurrence and recurrence of hepatocellular carcinoma after successful direct-acting antiviral therapy for patients with chronic hepatitis C virus infection. Gastroenterol Hepatol (N Y). 2017;13:421–5.

    Google Scholar 

  111. Saadoun D, Thibault V, Si Ahmed SN, Alric L, Mallet M, Guillaud C, et al. Sofosbuvir plus ribavirin for hepatitis C virus-associated cryoglobulinaemia vasculitis: VASCUVALDIC study. Ann Rheum Dis. 2016;75:1777–82.

    Article  CAS  PubMed  Google Scholar 

  112. Gragnani L, Visentini M, Fognani E, Urraro T, De Santis A, Petraccia L, et al. Prospective study of guideline-tailored therapy with direct-acting antivirals for hepatitis C virus-associated mixed cryoglobulinemia. Hepatology. 2016;64:1473–82.

    Article  CAS  PubMed  Google Scholar 

  113. Sollima S, Milazzo L, Peri AM, Torre A, Antinori S, Galli M. Persistent mixed cryoglobulinaemia vasculitis despite hepatitis C virus eradication after interferon-free antiviral therapy. Rheumatology (Oxford). 2016;55:2084–5.

    Article  Google Scholar 

  114. Bonacci M, Lens S, Londoño MC, Mariño Z, Cid MC, Ramos-Casals M, et al. Virologic, clinical, and immune response outcomes of patients with hepatitis C virus-associated cryoglobulinemia treated with direct-acting antivirals. Clin Gastroenterol Hepatol. 2017;15:575–83.

    Article  CAS  PubMed  Google Scholar 

  115. Lauletta G, Russi S, Pavone F, Vacca A, Dammacco F. Direct-acting antiviral agents in the therapy of hepatitis C virus-related mixed cryoglobulinaemia: a single-centre experience. Arthritis Res Ther. 2017;19:74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Emery JS, Kuczynski M, La D, Almarzooqi S, Kowgier M, Shah H, et al. Efficacy and safety of direct acting antivirals for the treatment of mixed cryoglobulinemia. Am J Gastroenterol. 2017;112:1298–308.

    Article  CAS  PubMed  Google Scholar 

  117. Saadoun D, Pol S, Ferfar Y, Alric L, Hezode C, Si Ahmed SN, et al. Efficacy and safety of sofosbuvir plus daclatasvir for treatment of HCV-associated cryoglobulinemia vasculitis. Gastroenterology. 2017;153:49–52.

    Article  CAS  PubMed  Google Scholar 

  118. Conti F, Buonfiglioli F, Scuteri A, Crespi C, Bolondi L, Caraceni P, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol. 2016;65:727–33.

    Article  CAS  PubMed  Google Scholar 

  119. Butt AS, Sharif F, Abid S. Impact of direct acting antivirals on occurrence and recurrence of hepatocellular carcinoma: biologically plausible or an epiphenomenon? World J Hepatol. 2018;10:267–76.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Roche B, Coilly A, Duclos-Vallee JC, Samuel D. The impact of treatment of hepatitis C with DAAs on the occurrence of HCC. Liver Int. 2018;38(Suppl 1):139–45.

    Article  PubMed  Google Scholar 

  121. Huang AC, Mehta N, Dodge JL, Yao FY, Terrault NA. Direct-acting antivirals do not increase the risk of hepatocellular carcinoma recurrence after local-regional therapy or liver transplant waitlist dropout. Hepatology. 2018. https://doi.org/10.1002/hep.29855 [Epub ahead of print].

    Article  PubMed  Google Scholar 

  122. Romano A, Angeli P, Piovesan S, Noventa F, Anastassopoulos G, Chemello L, et al. Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: a prospective population study. J Hepatol. 2018. https://doi.org/10.1016/j.jhep.2018.03.009 [Epub ahead of print].

    Article  PubMed  Google Scholar 

  123. Mascia MT, Ferrari D, Campioli D, Sandri G, Mussini C, Ferri C. Non HCV-related mixed cryoglobulinemia. Dig Liver Dis. 2007;39(Suppl 1):S61–4.

    Article  PubMed  Google Scholar 

  124. 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. 2015;65:74–81.

    Article  PubMed  Google Scholar 

  125. Galli M, Oreni L, Saccardo F, Castelnovo L, Filippini D, Marson P, et al. HCV-unrelated cryoglobulinaemic vasculitis: the results of a prospective observational study by the Italian Group for the Study of Cryoglobulinaemias (GISC). Clin Exp Rheumatol. 2017;35(Suppl 103):67–76.

    PubMed  Google Scholar 

  126. 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. 2012;119:5996–6004.

    Article  CAS  PubMed  Google Scholar 

  127. Spatola L, Generali E, Angelini C, Badalamenti S, Selmi C. HCV-negative mixed cryoglobulinemia and kidney involvement: in-depth review on physiopathological and histological bases. Clin Exp. Med 2018 (accepted for publication).

  128. Landau DA, Saadoun D, Halfon P, Martinot-Peignoux M, Marcellin P, Fois E, et al. Relapse of hepatitis C virus-associated mixed cryoglobulinemia vasculitis in patients with sustained viral response. Arthritis Rheum. 2008;58:604–11.

    Article  PubMed  Google Scholar 

  129. Roccatello D, Sciascia S, Rossi D, Solfietti L, Fenoglio R, Menegatti E, et al. The challenge of treating hepatitis C virus-associated cryoglobulinemic vasculitis in the era of anti-CD20 monoclonal antibodies and direct antiviral agents. Oncotarget. 2017;8:41764–77.

    PubMed  PubMed Central  Google Scholar 

  130. Cornella SL, Stine JG, Kelly V, Caldwell SH, Shah NL. 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;127:413–7.

    Article  PubMed  Google Scholar 

  131. Castillo JJ, Ghobrial IM, Treon SP. Biology, prognosis, and therapy of Waldenström Macroglobulinemia. Cancer Treat Res. 2015;165:177–95.

    Article  PubMed  Google Scholar 

  132. Chen LY, Shah R, Cwynarski K, Lambert J, McNamara C, Mohamedbhai SG, et al. Ofatumumab is a feasible alternative anti-CD20 therapy in patients intolerant of rituximab. Br J Haematol. 2018. https://doi.org/10.1111/bjh.15110 [Epub ahead of print].

    Article  PubMed  PubMed Central  Google Scholar 

  133. Merli M, Frigeni M, Gotti M, Grossi P, Bruno R, Passamonti F, et al. Direct-acting antivirals during or after immunochemotherapy in hepatitis C virus-positive diffuse large B-cell lymphomas. Hepatology. 2017;66:1341–3.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), Investigator Grant (No. 20441) to VR, Milan, Italy, and the Special Program Molecular Clinical Oncology 5 per 1000 (Grant No. 9965) to AV, Milan, Italy.

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Authors and Affiliations

  1. Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine, University of Bari “Aldo Moro”, Polyclinic, Piazza G. Cesare, 11, 70124, Bari, Italy

    Franco Dammacco, Gianfranco Lauletta, Patrizia Leone, Angelo Vacca & Vito Racanelli

  2. IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy

    Sabino Russi

  3. Department of Biomedical Sciences and Human Oncology, Section of Clinical and Molecular Oncology, University of Bari “Aldo Moro”, Bari, Italy

    Marco Tucci

  4. Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplant Unit, University of Bari “Aldo Moro”, Bari, Italy

    Carlo Manno

  5. Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

    Salvatore Monaco & Sergio Ferrari

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  1. Franco Dammacco
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  2. Gianfranco Lauletta
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  3. Sabino Russi
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  4. Patrizia Leone
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  5. Marco Tucci
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  7. Salvatore Monaco
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  8. Sergio Ferrari
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  9. Angelo Vacca
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  10. Vito Racanelli
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Contributions

FD, GL, AV, and VR made essential contributions to the conception and design of the review, and the analysis and interpretation of the data. SR, PL, MT, CM, SM, and SF were involved in data collection, analysis, and interpretation. FD drafted the manuscript. All authors gave final approval of the version to be published and accept their accountability for all aspects of the work.

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Correspondence to Franco Dammacco.

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The authors have no competing financial interests in relation to this work.

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Dammacco, F., Lauletta, G., Russi, S. et al. Clinical practice: hepatitis C virus infection, cryoglobulinemia and cryoglobulinemic vasculitis. Clin Exp Med 19, 1–21 (2019). https://doi.org/10.1007/s10238-018-0536-z

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