Abstract
BACKGROUND—Mixed cryoglobulinaemia is closely associated with hepatitis C virus (HCV) infection. AIM—To assess in a prospective open study the efficiency of interferon α treatment of cryoglobulinaemia, as reflected by the disappearance of cryoglobulins and clinical manifestations of the disease, and to analyse the factors predictive of a response to interferon. METHOD—Eighty seven consecutive patients with chronic hepatitis C treated for the first time with interferon at a dose of 3 × 106 international units three times a week for six months were studied. Forty three patients had cryoglobulins, which were responsible for clinical manifestations in 12. RESULTS—At the end of interferon treatment, cryoglobulins had disappeared in 39% of the patients. A clinical improvement (except for neuropathies) was observed in all patients. Six months after interferon treatment was stopped, the same rate of response (normal alanine aminotransferase values and undectable HCV RNA) was observed in patients with or without cryoglobulins. Only 14% of patients still had undetectable cryoglobulins, and all of them also had undetectable serum HCV RNA. The disappearance of cryoglobulins was found less frequently in patients with clinical symptoms than in asymptomatic ones, but the difference was not significant. Sustained responders were more often men, infected by genotype 2 or 3, with a lower pretreatment viral load. CONCLUSION—The presence of cryoglobulins does not seem to affect the response to interferon in HCV infected patients. The improvement in cryoglobulinaemia is strongly associated with a virological response, reinforcing the hypothesis of a direct role for HCV in the pathogenesis of this disease. Keywords: hepatitis C virus; chronic hepatitis C; cryoglobulinaemia; cryoglobulins; interferon.
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- Agnello V., Chung R. T., Kaplan L. M. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med. 1992 Nov 19;327(21):1490–1495. doi: 10.1056/NEJM199211193272104. [DOI] [PubMed] [Google Scholar]
- Agnello V. Hepatitis C virus infection and type II cryoglobulinemia: an immunological perspective. Hepatology. 1997 Dec;26(6):1375–1379. doi: 10.1053/jhep.1997.v26.ajhep0261375. [DOI] [PubMed] [Google Scholar]
- Bonomo L., Casato M., Afeltra A., Caccavo D. Treatment of idiopathic mixed cryoglobulinemia with alpha interferon. Am J Med. 1987 Oct;83(4):726–730. doi: 10.1016/0002-9343(87)90904-1. [DOI] [PubMed] [Google Scholar]
- Brouet J. C., Clauvel J. P., Danon F., Klein M., Seligmann M. Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med. 1974 Nov;57(5):775–788. doi: 10.1016/0002-9343(74)90852-3. [DOI] [PubMed] [Google Scholar]
- Cacoub P., Lunel F., Musset L., Opolon P., Piette J. C. Hepatitis C virus and cryoglobulinemia. N Engl J Med. 1993 Apr 15;328(15):1121–1124. [PubMed] [Google Scholar]
- Casato M., Agnello V., Pucillo L. P., Knight G. B., Leoni M., Del Vecchio S., Mazzilli C., Antonelli G., Bonomo L. Predictors of long-term response to high-dose interferon therapy in type II cryoglobulinemia associated with hepatitis C virus infection. Blood. 1997 Nov 15;90(10):3865–3873. [PubMed] [Google Scholar]
- 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 Dec 15;78(12):3142–3147. [PubMed] [Google Scholar]
- Causse X., Godinot H., Chevallier M., Chossegros P., Zoulim F., Ouzan D., Heyraud J. P., Fontanges T., Albrecht J., Meschievitz C. Comparison of 1 or 3 MU of interferon alfa-2b and placebo in patients with chronic non-A, non-B hepatitis. Gastroenterology. 1991 Aug;101(2):497–502. doi: 10.1016/0016-5085(91)90030-o. [DOI] [PubMed] [Google Scholar]
- Chemello L., Cavalletto L., Noventa F., Bonetti P., Casarin C., Bernardinello E., Pontisso P., Donada C., Casarin P., Belussi F. Predictors of sustained response, relapse and no response in patients with chronic hepatitis C treated with interferon-alpha. J Viral Hepat. 1995;2(2):91–96. doi: 10.1111/j.1365-2893.1995.tb00012.x. [DOI] [PubMed] [Google Scholar]
- Dammacco F., Sansonno D., Han J. H., Shyamala V., Cornacchiulo V., Iacobelli A. R., Lauletta G., Rizzi R. 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 Nov 15;84(10):3336–3343. [PubMed] [Google Scholar]
- Davis G. L., Balart L. A., Schiff E. R., Lindsay K., Bodenheimer H. C., Jr, Perrillo R. P., Carey W., Jacobson I. M., Payne J., Dienstag J. L. Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. Hepatitis Interventional Therapy Group. N Engl J Med. 1989 Nov 30;321(22):1501–1506. doi: 10.1056/NEJM198911303212203. [DOI] [PubMed] [Google Scholar]
- Di Bisceglie A. M., Martin P., Kassianides C., Lisker-Melman M., Murray L., Waggoner J., Goodman Z., Banks S. M., Hoofnagle J. H. Recombinant interferon alfa therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. N Engl J Med. 1989 Nov 30;321(22):1506–1510. doi: 10.1056/NEJM198911303212204. [DOI] [PubMed] [Google Scholar]
- Ferri C., Greco F., Longombardo G., Palla P., Moretti A., Marzo E., Fosella P. V., Pasero G., Bombardieri S. Antibodies to hepatitis C virus in patients with mixed cryoglobulinemia. Arthritis Rheum. 1991 Dec;34(12):1606–1610. doi: 10.1002/art.1780341221. [DOI] [PubMed] [Google Scholar]
- Ferri C., Marzo E., Longombardo G., Lombardini F., La Civita L., Vanacore R., Liberati A. M., Gerli R., Greco F., Moretti A. Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial. Blood. 1993 Mar 1;81(5):1132–1136. [PubMed] [Google Scholar]
- Frangeul L., Musset L., Cresta P., Cacoub P., Huraux J. M., Lunel F. Hepatitis C virus genotypes and subtypes in patients with hepatitis C, with and without cryoglobulinemia. J Hepatol. 1996 Oct;25(4):427–432. doi: 10.1016/s0168-8278(96)80200-5. [DOI] [PubMed] [Google Scholar]
- Gorevic P. D., Kassab H. J., Levo Y., Kohn R., Meltzer M., Prose P., Franklin E. C. Mixed cryoglobulinemia: clinical aspects and long-term follow-up of 40 patients. Am J Med. 1980 Aug;69(2):287–308. doi: 10.1016/0002-9343(80)90390-3. [DOI] [PubMed] [Google Scholar]
- Homberg J. C., Abuaf N., Bernard O., Islam S., Alvarez F., Khalil S. H., Poupon R., Darnis F., Lévy V. G., Grippon P. Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of "autoimmune" hepatitis. Hepatology. 1987 Nov-Dec;7(6):1333–1339. doi: 10.1002/hep.1840070626. [DOI] [PubMed] [Google Scholar]
- Hoofnagle J. H., Mullen K. D., Jones D. B., Rustgi V., Di Bisceglie A., Peters M., Waggoner J. G., Park Y., Jones E. A. Treatment of chronic non-A,non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med. 1986 Dec 18;315(25):1575–1578. doi: 10.1056/NEJM198612183152503. [DOI] [PubMed] [Google Scholar]
- Knodell R. G., Ishak K. G., Black W. C., Chen T. S., Craig R., Kaplowitz N., Kiernan T. W., Wollman J. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology. 1981 Sep-Oct;1(5):431–435. doi: 10.1002/hep.1840010511. [DOI] [PubMed] [Google Scholar]
- Levo Y., Gorevic P. D., Kassab H. J., Tobias H., Franklin E. C. Liver involvement in the syndrome of mixed cryoglobulinemia. Ann Intern Med. 1977 Sep;87(3):287–292. doi: 10.7326/0003-4819-87-3-287. [DOI] [PubMed] [Google Scholar]
- Lunel F., Cresta P., Vitour D., Payan C., Dumont B., Frangeul L., Reboul D., Brault C., Piette J. C., Huraux J. M. Comparative evaluation of hepatitis C virus RNA quantitation by branched DNA, NASBA, and monitor assays. Hepatology. 1999 Feb;29(2):528–535. doi: 10.1002/hep.510290237. [DOI] [PubMed] [Google Scholar]
- Lunel F., Musset L., Cacoub P., Frangeul L., Cresta P., Perrin M., Grippon P., Hoang C., Valla D., Piette J. C. Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology. 1994 May;106(5):1291–1300. doi: 10.1016/0016-5085(94)90022-1. [DOI] [PubMed] [Google Scholar]
- Marcellin P., Boyer N., Giostra E., Degott C., Courouce A. M., Degos F., Coppere H., Cales P., Couzigou P., Benhamou J. P. Recombinant human alpha-interferon in patients with chronic non-A, non-B hepatitis: a multicenter randomized controlled trial from France. Hepatology. 1991 Mar;13(3):393–397. [PubMed] [Google Scholar]
- Martini E., Abuaf N., Cavalli F., Durand V., Johanet C., Homberg J. C. Antibody to liver cytosol (anti-LC1) in patients with autoimmune chronic active hepatitis type 2. Hepatology. 1988 Nov-Dec;8(6):1662–1666. doi: 10.1002/hep.1840080632. [DOI] [PubMed] [Google Scholar]
- Martinot-Peignoux M., Marcellin P., Pouteau M., Castelnau C., Boyer N., Poliquin M., Degott C., Descombes I., Le Breton V., Milotova V. Pretreatment serum hepatitis C virus RNA levels and hepatitis C virus genotype are the main and independent prognostic factors of sustained response to interferon alfa therapy in chronic hepatitis C. Hepatology. 1995 Oct;22(4 Pt 1):1050–1056. [PubMed] [Google Scholar]
- Meltzer M., Franklin E. C., Elias K., McCluskey R. T., Cooper N. Cryoglobulinemia--a clinical and laboratory study. II. Cryoglobulins with rheumatoid factor activity. Am J Med. 1966 Jun;40(6):837–856. doi: 10.1016/0002-9343(66)90200-2. [DOI] [PubMed] [Google Scholar]
- Misiani R., Bellavita P., Fenili D., Vicari O., Marchesi D., Sironi P. L., Zilio P., Vernocchi A., Massazza M., Vendramin G. Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med. 1994 Mar 17;330(11):751–756. doi: 10.1056/NEJM199403173301104. [DOI] [PubMed] [Google Scholar]
- Musset L., Diemert M. C., Taibi F., Thi Huong Du L., Cacoub P., Leger J. M., Boissy G., Gaillard O., Galli J. Characterization of cryoglobulins by immunoblotting. Clin Chem. 1992 Jun;38(6):798–802. [PubMed] [Google Scholar]
- Pascual M., Perrin L., Giostra E., Schifferli J. A. Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis. 1990 Aug;162(2):569–570. doi: 10.1093/infdis/162.2.569. [DOI] [PubMed] [Google Scholar]
- Stuyver L., Rossau R., Wyseur A., Duhamel M., Vanderborght B., Van Heuverswyn H., Maertens G. Typing of hepatitis C virus isolates and characterization of new subtypes using a line probe assay. J Gen Virol. 1993 Jun;74(Pt 6):1093–1102. doi: 10.1099/0022-1317-74-6-1093. [DOI] [PubMed] [Google Scholar]
- Urdea M. S., Horn T., Fultz T. J., Anderson M., Running J. A., Hamren S., Ahle D., Chang C. A. Branched DNA amplification multimers for the sensitive, direct detection of human hepatitis viruses. Nucleic Acids Symp Ser. 1991;(24):197–200. [PubMed] [Google Scholar]
- Van Thiel D. H., Fagiuoli S., Caraceni P., Wright H. I., Nadir A., Gavaler J. S., Zuhdi N. Cryoglobulinemia: a cause for false negative polymerase chain reaction results in patients with hepatitis C virus positive chronic liver disease. J Hepatol. 1995 Apr;22(4):464–467. doi: 10.1016/0168-8278(95)80110-3. [DOI] [PubMed] [Google Scholar]
- Zarski J. P., Rougier D., Aubert H., Renversez J. C., Cordonnier D., Stoebner P., Rachail M. Association cryoglobuline et maladie hépatique: fréquence, nature et caractères immuno-chimiques de la cryoglobulinémie. Gastroenterol Clin Biol. 1984 Nov;8(11):845–850. [PubMed] [Google Scholar]