Mixed cryoglobulinemia in chronic hepatitis C: transformation of perceptions in the context of modern antiviral therapy
AbstractMixed cryoglobulinemia is the most frequent extrahepatic manifestation of chronic hepatitis C virus, which develops as a result of progressive lymphoproliferative disorders induced by the virus persistent stimulation of immunocompetent cells, primarily, B-lymphocytes. Lymphoproliferation clinical manifestations involve B-cell non-Hodgkin lymphoma and cryoglobulinemic vasculitis, in the pathogenesis of which there are also elements of autoimmunity activation. Antiviral therapy with direct-acting agents enables hepatitis C elimination in almost all treated patients. With a sustainable virologic response, most patients develop a complete or partial cryoglobulinemic vasculitis remission, sometimes without any concomitant immunosuppressive treatment. Cryoglobulin production is occasionally suppressed. Less frequently, such disease associated immunological signs as an increased level of rheumatoid factor and a reduced concentration of complement C4 are normalized. The review covers pathogenesis, clinical manifestations, general principles and outcomes of lymphoproliferative disorders therapy, in particular, the treatment of cryoglobulinemic vasculitis, associated with chronic HCV infection in the era of modern antiviral therapy. Additionally, the review hypothesizes possible consequences of persistent cryoglobulinemia after the successful management of chronic HCV.
Keywords:chronic hepatitis C; lymphoproliferation; mixed cryoglobulinemia; B-cell non-Hodgkin lymphoma; antiviral therapy; immunosuppressive therapy
Funding. The study had no financial support.
Conflict of interest. The authors declare no conflict of interest.
Contribution. Сoncept and design – Zubkin M.L., Semenenko T.A., Kryukov E.V.; text writing – Semenenko T.A., Zubkin M.L., Chervinko V.I., Frolova N.F., Konopleva N.V., Kryukov E.V.; approval of the final version of the article – Zubkin M.L., Semenenko T.A., Kryukov E.V.; responsibility for the integrity of all parts of the article – Zubkin M.L., Chervinko V.I., Kryukov E.V.
For citation: Zubkin M.L., Semenenko T.A., Chervinko V.I., Frolova N.F., Konopleva N.V., Kryukov E.V. Mixed cryoglobulinemia in chronic hepatitis C: transformation of perceptions in the context of modern antiviral therapy. Infektsionnye bolezni: novosti, mneniya, obuchenie [Infectious Diseases: News, Opinions, Training]. 2022; 11 (3): 138–50. DOI: https://doi.org/10.33029/2305-3496-2022-11-3-138-150
References
1. Brouet J.C., Clauvel J.P., Danon F., et al. Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med. 1974; 57 (5): 775–88. DOI: https://doi.org/10.1016/0002-9343(74)90852-3
2. Terrier B., Karras A., Kahn J.E., et al. The spectrum of type I cryoglobulinemia vasculitis: new insights based on 64 cases. Medicine (Baltimore). 2013; 92: 61–8. DOI: https://doi.org/10.1097/MD.0b013e318288925c
3. Davuluri S., Bansal P. Cryoglobulinemic vasculitis. In: StatPearls [Internet]. Treasure Island, FL: Stat Pearls Publishing, 2021 Jan 22. PMID: 32310505.
4. Basile U., Napodano C., Marino M., et al. Cryoglobulins: putative effectors of adaptive immune response. Clin Exp Rheumatol. 2021; 39 (2): 171–9. PMID: 33124568
5. Bunchorntavakul C., Mitraniy R., Reddy K.R. Advances in HCV and cryoglobulinemic vasculitis in the era of DAAs: are we at the end of the road? J Clin Exp Hepatol. 2018; 8 (1): 81–94. DOI: https://doi.org/10.1016 / j.jceh.2017.11.012
6. Aguiar M.F., Faria-Janes A.L., Garcia-Brandes G.I., et al. Prevalence of cryoglobulinemia and cryoglobulinemic vasculitis in chronically HCV-infected Brazilian patients. Ann Hepatol. 2019; 18 (5): 685–92. DOI: https://doi.org/10.1016/j.aohep.2019.04.010
7. Boleto G., Ghillani-Dalbin P., Musset L., et al. Cryoglobulinemia after the era of chronic hepatitis C infection. Semin Arthritis Rheum. 2020; 50 (4): 695–700. DOI: https://doi.org/10.1016/j.semarthrit.2020.05.004
8. Caviglia G.P., Sciacca C., Abate M.L., et al. Chronic hepatitis C virus infection and lymphoproliferative disorders: mixed cryoglobulinemia syndrome, monoclonal gammopathy of undetermined significance, and B-cell non-Hodgkin lymphoma. J Gastroenterol Hepatol. 2015; 30 (4): 742–7. DOI: https://doi.org/10.1111/jgh.12837
9. Dammacco F., Racanelli V., Russi S., Sansonno D. The expanding spectrum of HCV-related cryoglobulinemic vasculitis: a narrative review. Clin Exp Med. 2016; 16 (3): 233–42. DOI: https://doi.org/10.1007/s10238-016-0410-9
10. De Vita S., Quartuccio L., Fabris M. Hepatitis C virus infection, mixed cryoglobulinemia and BLyS upregulation: targeting the infectious trigger, the autoimmune response, or both? Autoimmun Rev. 2008; 8 (2): 95–9. DOI: https://doi.org/10.1016/j.autrev.2008.05.005
11. Dammacco F., Lauletta G., Russi S., et al. Clinical practice: hepatitis C virus infection, cryoglobulinemia and cryoglobulinemic vasculitis. Clin Exp Med. 2019; 19 (1): 1–21. DOI: https://doi.org/10.1007/s10238-018-0536-z
12. Smulski C.R., Eibel H. BAFF and BAFF-receptor in B cell selection and survival. Front Immunol. 2018; 9: 2285. DOI: https://doi.org/10.3389/fimmu.2018.02285
45. Landau D.-A., Saadoun D., Halfon Ph., et al. Relapse of hepatitis C virus-associated mixed cryoglobulinemia vasculitis in patients with sustained viral response. Arthritis Rheum. 2008; 58 (2): 604–11. DOI: https://doi.org/10.1002/art.23305
46. Del Padre M., Todi L., Mitrevski M., et al. Reversion of anergy signatures in clonal CD21low B cells of mixed cryoglobulinemia after clearance of HCV viremia. Blood. 2017; 130 (1): 35–8. DOI: https://doi.org/10.1182/blood-2017-03-77128
47. Sang A., Niu H., Cullen J., et al. Activation of rheumatoid factor-specific B cells is antigen dependent and occurs preferentially outside of germinal centers in the lupusprone NZM2410 mouse model. J Immunol. 2014; 193 (4): 1609–21. DOI: https://doi.org/10.4049/jimmunol.1303000
48. Giannelli F., Moscarella S., Giannini C. Effect of antiviral treatment in patients with chronic HCV infection and t(14;18) translocation. Blood. 2003; 102 (4): 1196–201. DOI: https://doi.org/10.1182/blood-2002-05-1537
49. Chowdhury R., Tsen A. Recurrent mixed cryoglobulinemia despite sustained virologic response to treatment: a case report. Am J Kidney Dis. 2017; 70 (2): 301–4. DOI: https://doi.org/10.1053/j.ajkd.2017.01.041
50. Bichard P., Ounanian A., Girard M., et al. High prevalence of hepatitis C virus RNA in the supernatant and the cryoprecipitate of patients with essential and secondary type II mixed cryoglobulinemia. J Hepatol. 1994; 21 (1): 58–63. DOI: https://doi.org/10.1016/s0168-8278(94)80137-1
51. Arcaini L., Besson C., Frigeni M., et al. Interferon-free antiviral treatment in B-cell lymphoproliferative disorders associated with hepatitis C virus infection. Blood. 2016; 128 (21): 2527–32. DOI: https://doi.org/10.1182/blood-2016-05-714667
52. Ferri C. Feld J.J., Bondin M., Cacoub P. Expert opinion on managing chronic HCV in patients with non-Hodgkin lymphoma and other extrahepatic malignancies. Antivir Ther. 2018; 23 (2): 23–33. DOI: https://doi.org/10.3851/IMP3250
53. Merli M., Carli G., Arcaini L., Visco C. Antiviral therapy of hepatitis C as curative treatment of indolent B-cell lymphoma. World J Gastroenterol. 2016; 22 (38): 8447–58. DOI: https://doi.org/10.3748/wjg.v22.i38.8447
54. Visentini M., Fiorilli M., Casato M. From the pathogenesis to the cure of indolent B-cell lymphoproliferative disorders associated with hepatitis C virus infection: which role for direct-acting antivirals? Expert Rev Hematol. 2017; 10 (8): 719–27. DOI: https://doi.org/10.1080/17474086.2017.1349607
55. Alric L., Jaccard A., Pol S., et al. Antiviral treatment of HCV-infected patients with B-cell non-Hodgkin lymphoma. PLoS One. 2016; 11 (10): e0162965. DOI: https://doi.org/10.1371/journal.pone.0162965
56. Frigeni M., Besson C., Visco C., et al. Interferon-free compared to interferon-based antiviral regimens as first-line therapy for B-cell lymphoproliferative disorders associated with hepatitis C virus infection. Leukemia. 2020; 34 (5): 1462–6. DOI: https://doi.org/10.1038/s41375-019-0687-2
57. Santoriello D., Pullela N.K., Uday K.A., et al. Persistent hepatitis C virus-associated cryoglobulinemic glomerulonephritis in patients successfully treated with direct-acting antiviral therapy. Kidney Int Rep. 2018; 3 (4): 985–90. DOI: https://doi.org/10.1016/j.ekir.2018.03.016
58. Tasleem S., Sood G.K. Hepatitis C associated B-cell non-Hodgkin lymphoma: clinical features and the role of antiviral therapy. J Clin Transl Hepatol. 2015; 3 (2) 134–9. DOI: https://doi.org/10.14218/JCTH.2015.00011