- Email: [email protected]
Polyarteritis nodosa after interferon treatment for chronic hepatitis C
Journal of Clinical Virology 32 (2005) 181–182
Letter to the Editor
Polyarteritis nodosa after interferon treatment for chronic hepatitis C
Keywords: Hepatitis C; Interferon ␣; Side effects; Autoimmunity; Vasculitis; Polyarteritis nodosa
The importance of cryoglobulinaemia among the extrahepatic manifestations of hepatitis C infection is pointed out in a recent article of the journal (Dezzutti et al., 2004). They also emphasise the variability of its clinical expression. A characteristic picture associated to cryoglobulinaemia is vasculitis, most often a small-size leukocytoclastic vasculitis (Fabris et al., 2003; Lamprecht et al., 2001; Leone et al., 2002). On the other hand, autoimmune manifestations usually improve with the treatment of hepatitis that currently includes interferon (Cacoub et al., 2002; Naarendorp et al., 2001). Paradoxically an exacerbation of autoimmune disorders may also be caused by interferon (Wilson et al., 2002) usually shortly after starting interferon treatment (Boonyapisit and Katirji, 2002; Friedman et al., 1999; Gordon et al., 1998). Among them, a few polyarteritis nodosa (PAN) cases have been described too (Cacoub et al., 2001). We described a patient with chronic hepatitis C treated with pegylated interferon and ribavirin, who developed a PAN-like vasculitis without cryoglobulinaemia after stopping this treatment. A 35-year-old man, who had been addicted to intravenous drugs for one year 17 years ago, was diagnosed of chronic hepatitis C, genotype 3, in 1997. Antibodies against the human immunodeficiency virus were negative in repeated tests. In January 2003 he started a 24-week treatment with pegylated ␣2b interferon (Pegintron® ) and ribavirin. This was relatively well tolerated and effective: aminotransferase returned to normal values and plasma virus C RNA became undetectable. However, two weeks after stopping treatment he began to experience fever (up to 39 ◦ C), weight loss, intense and diffuse myalgias, peripheral oedema, erythematous nodules and livedo reticularis in extremities and bilateral orchitis. Haematological counts were normal. The erythrocyte sedimentation rate was 75 mm first hour. Biochemistry showed increased creatinine kinase (highest value 470 IU/l) and ␣2 and ␥-globulins. Complement components C4 and C3c, rheumatoid factor, antinuclear and anti-neutrophile1386-6532/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jcv.2004.10.003
cytoplasm antibodies were normal or negative. Two careful investigations for cryoglobulins were negative. Thyroid function tests were TSH 59.19 U/ml and free T4 below 0.4 ng/dl. In addition, thyroid peroxidase and thyroglobulin antibodies were positive, above 3000 and 1000 IU/ml, respectively. The hepatitis C viral RNA remained undetectable. Hepatitis B serological test indicated old infection (negative HbsAg, positive HBc antibody). Tests for syphilis, brucella, human immmunodeficiency and Epstein-Barr virus were negative. Thorax X-ray and abdominal ultrasonography did not show any abnormalities. A cutaneous biopsy demonstrated typical signs of a small and medium diameter necrotising vasculitis (PAN). After starting a daily treatment with 60 mg of prednisone, fever disappeared and myalgias, cutaneous nodules and orchitis progressively improved. Steroids were slowly tapered, and the patient remained free of symptoms. After a 12-month follow-up the patient remained well, his liver function tests were normal and plasma C virus RNA was undetectable. The potential relationship of the appearance of systemic PAN in the context of the evolution of hepatitis C and its treatment in this case deserves several comments. First, the most common form of hepatitis C-associated vasculitis is type II mixed cryoglobulinaemia. However, PAN without cryoglobulins has also been described, although exceptionally (Cacoub et al., 2001). In our patient, virus C was undetectable and cryoglobulinaemia was not found. Therefore, it seems unlikely that PAN was a non-hepatic manifestation of hepatitis C virus infection. Indeed, autoimmune thyroid disease and PAN developed at a moment when liver disease was fully controlled. A more plausible explanation is that both disorders could be related to the treatment with interferon. The excellent evolution of both conditions is an additional argument in favour of this relationship. The exacerbation of autoimmune diseases is a well-known consequence of the treatment with ␣-interferon and other cytokines. A correlation between interferon serum levels and
182
Letter to the Editor / Journal of Clinical Virology 32 (2005) 181–182
clinical activity in autoimmune diseases has been described. Furthermore, interferon therapy may exacerbate autoimmunity by up-regulating class I and II major histocompatibility complex antigens, ␥ interferon, and Bcl-2 oncogene expression, the latter interfering with the normal elimination of autoreactive B cells by apoptosis. Autoimmune side effects usually occur during interferon therapy within a few weeks after starting therapy. In spite of this, infrequent cases have been observed several years after initiation of therapy or even after its discontinuation (Wilson et al., 2002). We were fortunate with the good response of our patient to prednisone treatment. Steroids may potentially exacerbate virus replication and hepatitis, but this did not happen in this case, further suggesting that virus C infection was fully controlled. On the other hand, if vasculitis had not been controlled we would have needed a more aggressive regime with plasmapheresis and immunosuppressive therapy (Guillevin and Cohen, 2002). In any case, this patient is an example of a highly complex situation, where an antiviral biologic agent might be at the same time the best available therapy and a pathogenic factor.
References Boonyapisit K, Katirji B. Severe exacerbation of hepatitis C-associated vasculitic neuropathy following treatment with interferon alpha: a case report and literature review. Muscle Nerve 2002;25:909–13. Cacoub P, Lidove O, Maisonobe T, Duhaut P, Thibault V, Ghillani P, et al. Interferon-alpha and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis. Arthritis Rheum 2002;46:3317–26. Cacoub P, Maisonobe T, Thibault V, Gatel A, Servan J, Musset L, et al. Systemic vasculitis in patients with hepatitis C. J Rheumatol 2001;28:109–18. Dezzutti CS, Astemborski J, Thomas DL, Marshall JH, Cabrera T, Purdy M, et al. Prevalence of cryoglobulinemia in hepatitis C virus (HCV) positive patients with and without human immunodeficiency virus (HIV) coinfection. J Clin Virol 2004;31:210–4. Fabris P, Tositti G, Giordani MT, Romano L, Betterle C, Pignattari E, et al. Prevalence and clinical significance of circulating cryoglobulins in
HIV-positive patients with and without co-infection with hepatitis C virus. J Med Virol 2003;69:339–43. Friedman G, Mehta S, Sherker AH. Fatal exacerbation of hepatitis Crelated cryoglobulinemia with interferon-alpha therapy. Dig Dis Sci 1999;44:1364–5. Gordon AC, Edgar JD, Finch RG. Acute exacerbation of vasculitis during interferon-alpha therapy for hepatitis C-associated cryoglobulinaemia. J Infect 1998;36:229–30. Guillevin L, Cohen P. Management of virus-induced systemic vasculitides. Curr Rheumatol Rep 2002;4:60–6. Lamprecht P, Moosig F, Gause A, Herlyn K, Csernok E, Hansen H, et al. Immunological and clinical follow up of hepatitis C virus associated cryoglobulinaemic vasculitis. Ann Rheum Dis 2001;60:385–90. Leone N, Pellicano R, Ariata MI, Modena V, Marietti G, Rizzetto M, et al. Mixed cryoglobulinaemia and chronic hepatitis C virus infection: the rheumatic manifestations. J Med Virol 2002;66:200–3. Naarendorp M, Kallemuchikkal U, Nuovo GJ, Gorevic PD. Longterm efficacy of interferon-alpha for extrahepatic disease associated with hepatitis C virus infection. J Rheumatol 2001;28:2466–73. Wilson LE, Widman D, Dikman SH, Gorevic PD. Autoimmune disease complicating antiviral therapy for hepatitis C virus infection. Semin Arthritis Rheum 2002;32:163–73.
Juan de Dios Garc´ıa-D´ıaz∗ Marta Garc´ıa-S´anchez Pilar Arcos Internal Medicine Department, Hospital Universitario Pr´ıncipe de Asturias, Universidad de Alcal´a Ctra. Alcal´a-Meco, s/n Alcal´a de Henares 28805 Madrid, Spain Jos´e Ignacio Busteros Pathology Department, Hospital Universitario Pr´ıncipe de Asturias, Universidad de Alcal´a Alcal´a de Henares, 28805 Madrid, Spain ∗ Corresponding
author Tel.: +34 91 88 78100x2635; fax: +34 91 88 01825 E-mail address: [email protected] (J. de Dios Garc´ıa-D´ıaz) 2 September 2004
Letter to the Editor
Polyarteritis nodosa after interferon treatment for chronic hepatitis C
Keywords: Hepatitis C; Interferon ␣; Side effects; Autoimmunity; Vasculitis; Polyarteritis nodosa
The importance of cryoglobulinaemia among the extrahepatic manifestations of hepatitis C infection is pointed out in a recent article of the journal (Dezzutti et al., 2004). They also emphasise the variability of its clinical expression. A characteristic picture associated to cryoglobulinaemia is vasculitis, most often a small-size leukocytoclastic vasculitis (Fabris et al., 2003; Lamprecht et al., 2001; Leone et al., 2002). On the other hand, autoimmune manifestations usually improve with the treatment of hepatitis that currently includes interferon (Cacoub et al., 2002; Naarendorp et al., 2001). Paradoxically an exacerbation of autoimmune disorders may also be caused by interferon (Wilson et al., 2002) usually shortly after starting interferon treatment (Boonyapisit and Katirji, 2002; Friedman et al., 1999; Gordon et al., 1998). Among them, a few polyarteritis nodosa (PAN) cases have been described too (Cacoub et al., 2001). We described a patient with chronic hepatitis C treated with pegylated interferon and ribavirin, who developed a PAN-like vasculitis without cryoglobulinaemia after stopping this treatment. A 35-year-old man, who had been addicted to intravenous drugs for one year 17 years ago, was diagnosed of chronic hepatitis C, genotype 3, in 1997. Antibodies against the human immunodeficiency virus were negative in repeated tests. In January 2003 he started a 24-week treatment with pegylated ␣2b interferon (Pegintron® ) and ribavirin. This was relatively well tolerated and effective: aminotransferase returned to normal values and plasma virus C RNA became undetectable. However, two weeks after stopping treatment he began to experience fever (up to 39 ◦ C), weight loss, intense and diffuse myalgias, peripheral oedema, erythematous nodules and livedo reticularis in extremities and bilateral orchitis. Haematological counts were normal. The erythrocyte sedimentation rate was 75 mm first hour. Biochemistry showed increased creatinine kinase (highest value 470 IU/l) and ␣2 and ␥-globulins. Complement components C4 and C3c, rheumatoid factor, antinuclear and anti-neutrophile1386-6532/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jcv.2004.10.003
cytoplasm antibodies were normal or negative. Two careful investigations for cryoglobulins were negative. Thyroid function tests were TSH 59.19 U/ml and free T4 below 0.4 ng/dl. In addition, thyroid peroxidase and thyroglobulin antibodies were positive, above 3000 and 1000 IU/ml, respectively. The hepatitis C viral RNA remained undetectable. Hepatitis B serological test indicated old infection (negative HbsAg, positive HBc antibody). Tests for syphilis, brucella, human immmunodeficiency and Epstein-Barr virus were negative. Thorax X-ray and abdominal ultrasonography did not show any abnormalities. A cutaneous biopsy demonstrated typical signs of a small and medium diameter necrotising vasculitis (PAN). After starting a daily treatment with 60 mg of prednisone, fever disappeared and myalgias, cutaneous nodules and orchitis progressively improved. Steroids were slowly tapered, and the patient remained free of symptoms. After a 12-month follow-up the patient remained well, his liver function tests were normal and plasma C virus RNA was undetectable. The potential relationship of the appearance of systemic PAN in the context of the evolution of hepatitis C and its treatment in this case deserves several comments. First, the most common form of hepatitis C-associated vasculitis is type II mixed cryoglobulinaemia. However, PAN without cryoglobulins has also been described, although exceptionally (Cacoub et al., 2001). In our patient, virus C was undetectable and cryoglobulinaemia was not found. Therefore, it seems unlikely that PAN was a non-hepatic manifestation of hepatitis C virus infection. Indeed, autoimmune thyroid disease and PAN developed at a moment when liver disease was fully controlled. A more plausible explanation is that both disorders could be related to the treatment with interferon. The excellent evolution of both conditions is an additional argument in favour of this relationship. The exacerbation of autoimmune diseases is a well-known consequence of the treatment with ␣-interferon and other cytokines. A correlation between interferon serum levels and
182
Letter to the Editor / Journal of Clinical Virology 32 (2005) 181–182
clinical activity in autoimmune diseases has been described. Furthermore, interferon therapy may exacerbate autoimmunity by up-regulating class I and II major histocompatibility complex antigens, ␥ interferon, and Bcl-2 oncogene expression, the latter interfering with the normal elimination of autoreactive B cells by apoptosis. Autoimmune side effects usually occur during interferon therapy within a few weeks after starting therapy. In spite of this, infrequent cases have been observed several years after initiation of therapy or even after its discontinuation (Wilson et al., 2002). We were fortunate with the good response of our patient to prednisone treatment. Steroids may potentially exacerbate virus replication and hepatitis, but this did not happen in this case, further suggesting that virus C infection was fully controlled. On the other hand, if vasculitis had not been controlled we would have needed a more aggressive regime with plasmapheresis and immunosuppressive therapy (Guillevin and Cohen, 2002). In any case, this patient is an example of a highly complex situation, where an antiviral biologic agent might be at the same time the best available therapy and a pathogenic factor.
References Boonyapisit K, Katirji B. Severe exacerbation of hepatitis C-associated vasculitic neuropathy following treatment with interferon alpha: a case report and literature review. Muscle Nerve 2002;25:909–13. Cacoub P, Lidove O, Maisonobe T, Duhaut P, Thibault V, Ghillani P, et al. Interferon-alpha and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis. Arthritis Rheum 2002;46:3317–26. Cacoub P, Maisonobe T, Thibault V, Gatel A, Servan J, Musset L, et al. Systemic vasculitis in patients with hepatitis C. J Rheumatol 2001;28:109–18. Dezzutti CS, Astemborski J, Thomas DL, Marshall JH, Cabrera T, Purdy M, et al. Prevalence of cryoglobulinemia in hepatitis C virus (HCV) positive patients with and without human immunodeficiency virus (HIV) coinfection. J Clin Virol 2004;31:210–4. Fabris P, Tositti G, Giordani MT, Romano L, Betterle C, Pignattari E, et al. Prevalence and clinical significance of circulating cryoglobulins in
HIV-positive patients with and without co-infection with hepatitis C virus. J Med Virol 2003;69:339–43. Friedman G, Mehta S, Sherker AH. Fatal exacerbation of hepatitis Crelated cryoglobulinemia with interferon-alpha therapy. Dig Dis Sci 1999;44:1364–5. Gordon AC, Edgar JD, Finch RG. Acute exacerbation of vasculitis during interferon-alpha therapy for hepatitis C-associated cryoglobulinaemia. J Infect 1998;36:229–30. Guillevin L, Cohen P. Management of virus-induced systemic vasculitides. Curr Rheumatol Rep 2002;4:60–6. Lamprecht P, Moosig F, Gause A, Herlyn K, Csernok E, Hansen H, et al. Immunological and clinical follow up of hepatitis C virus associated cryoglobulinaemic vasculitis. Ann Rheum Dis 2001;60:385–90. Leone N, Pellicano R, Ariata MI, Modena V, Marietti G, Rizzetto M, et al. Mixed cryoglobulinaemia and chronic hepatitis C virus infection: the rheumatic manifestations. J Med Virol 2002;66:200–3. Naarendorp M, Kallemuchikkal U, Nuovo GJ, Gorevic PD. Longterm efficacy of interferon-alpha for extrahepatic disease associated with hepatitis C virus infection. J Rheumatol 2001;28:2466–73. Wilson LE, Widman D, Dikman SH, Gorevic PD. Autoimmune disease complicating antiviral therapy for hepatitis C virus infection. Semin Arthritis Rheum 2002;32:163–73.
Juan de Dios Garc´ıa-D´ıaz∗ Marta Garc´ıa-S´anchez Pilar Arcos Internal Medicine Department, Hospital Universitario Pr´ıncipe de Asturias, Universidad de Alcal´a Ctra. Alcal´a-Meco, s/n Alcal´a de Henares 28805 Madrid, Spain Jos´e Ignacio Busteros Pathology Department, Hospital Universitario Pr´ıncipe de Asturias, Universidad de Alcal´a Alcal´a de Henares, 28805 Madrid, Spain ∗ Corresponding
author Tel.: +34 91 88 78100x2635; fax: +34 91 88 01825 E-mail address: [email protected] (J. de Dios Garc´ıa-D´ıaz) 2 September 2004