A 42-year-old female who was an asymptomatic carrier of hepatitis B virus (HBV) was diagnosed with antineutrophil cytoplasm antibody- (ANCA-) associated vasculitis and was induced to remission with 30？mg/day prednisolone nine years ago. Four years ago, she suffered recurrence of ANCA-associated vasculitis and with 30？mg/day prednisolone was induced to remission. This time, laboratory data showed 3-fold increase in myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) levels. Administration of 30？mg/day prednisolone was started. Three days later, she was admitted to our hospital suffering from fatigue. After admission, urinalysis showed glomerular hematuria. Despite administration of 30？mg/day prednisolone, MPO-ANCA titer had been of high level, ranging from 42 to 83 EU for 2.5 months. Furthermore, the adverse effects of steroid were seen. We decided the tapering of prednisolone (25？mg/day) and the start of mizoribine (4-carbamoyl-1-β-D-ribofuranosyl imidazolium-5-olate) administration. After mizoribine treatment, MPO-ANCA titer was decreased without any mizoribine-related adverse effects. Six months later, MPO-ANCA titer was decreased to normal levels and she was induced to clinical remission without reactivation of HBV. We describe the effectiveness of mizoribine for the ANCA-associated vasculitis complicated with HBV-carrier. 1. Introduction The common treatment for antineutrophil cytoplasm antibody- (ANCA-) associated vasculitis is oral cyclophosphamide-corticosteroid combination therapy. However, there are some reports that cyclophosphamide-corticosteroid combination therapy has serious complications such as increased risk of infection, leucopenia, osteoporosis, diabetes, and sterility and malignancy [1–4]. Reactivation of hepatitis B virus (HBV) replication is one of complications in patients with chronic HBV infection who receive immunosuppressive therapy [5]. Mizoribine (4-carbamoyl-1-β-D-ribofuranosyl imidazololium-5-olate), a purine synthesis inhibitor, has an immunosuppressive effect equivalent to that of azathioprine, but with less hepatic toxicity and myelosuppression [6]. Mizoribine and mycophenolic acid inhibit the rate-limiting enzyme inosine monophosphate dehydrogenase (IMPDH) in the de novo pathway of purine biosynthesis. It was reported that IMPDH inhibitors have potential antiviral effect in vitro and inhibited HBV replication with cultures of primary human hepatocytes, HepG2 2.2.15 cells [7–12]. There have been some reports that mizoribine is useful not only as a preemptive treatment to prevent relapse, but as also an
References
[1]
J. Turnbull and L. Harper, “Adverse effects of therapy for ANCA-associated vasculitis,” Best Practice and Research: Clinical Rheumatology, vol. 23, no. 3, pp. 391–401, 2009.
[2]
H. Nawata, S. Soen, R. Takayanagi et al., “Guidelines on the management and treatment of glucocorticoid-induced osteoporosis of the Japanese Society for Bone and Mineral Research (2004),” Journal of Bone and Mineral Metabolism, vol. 23, no. 2, pp. 105–109, 2005.
[3]
M. C. Park, Y. B. Park, S. Y. Jung, I. H. Chung, K. H. Choi, and S. K. Lee, “Risk of ovarian failure and pregnancy outcome in patients with lupus nephritis treated with intravenous cyclophosphamide pulse therapy,” Lupus, vol. 13, no. 8, pp. 569–574, 2004.
[4]
J. E. Hader, L. Marzella, R. A. M. Myers, S. C. Jacobs, and M. J. Naslund, “Hyperbaric oxygen treatment for experimental cyclophosphamide-induced hemorrhagic cystitis,” Journal of Urology, vol. 149, no. 6, pp. 1617–1621, 1993.
[5]
A. S. F. Lok, R. H. S. Liang, E. K. W. Chiu, K. L. Wong, T. K. Chan, and D. Todd, “Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy: report of a prospective study,” Gastroenterology, vol. 100, no. 1, pp. 182–188, 1991.
[6]
K. Sonda, K. Takahashi, K. Tanabe et al., “Clinical pharmacokinetic study of mizoribine in renal transplantation patients,” Transplantation Proceedings, vol. 28, no. 6, pp. 3643–3648, 1996.
[7]
H. Ichimura and J. A. Levy, “Polymerase substrate depletion: a novel strategy for inhibiting the replication of the human immunodeficiency virus,” Virology, vol. 211, no. 2, pp. 554–560, 1995.
[8]
Z. J. Gong, S. De Meyer, C. Clarysse et al., “Mycophenolic acid, an immunosuppressive agent, inhibits HBV replication in vitro,” Journal of Viral Hepatitis, vol. 6, no. 3, pp. 229–236, 1999.
[9]
P. Franchetti and M. Grifantini, “Nucleoside and non-nucleoside IMP dehydrogenase inhibitors as antitumor and antiviral agents,” Current Medicinal Chemistry, vol. 6, no. 7, pp. 599–614, 1999.
[10]
E. Padalko, E. Verbeken, P. Matthys, J. L. Aerts, E. De Clercq, and J. Neyts, “Mycophenolate mofetil inhibits the development of Coxsackie B3-virus-induced myocarditis in mice,” BMC Microbiology, vol. 3, article 25, 2003.
[11]
M. C. Livonesi, R. L. Moro De Sousa, and L. T. Moraes Figueiredo, “In vitro study of antiviral activity of mycophenolic acid on Brazilian orthobunyaviruses,” Intervirology, vol. 50, no. 3, pp. 204–208, 2007.
[12]
W. Markland, T. J. Mcquaid, J. Jain, and A. D. Kwong, “Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX- 497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon,” Antimicrobial Agents and Chemotherapy, vol. 44, no. 4, pp. 859–866, 2000.
[13]
K. Hirayama, M. Kobayashi, Y. Hashimoto et al., “Treatment with the purine synthesis inhibitor mizoribine for ANCA-associated renal vasculitis,” American Journal of Kidney Diseases, vol. 44, no. 1, pp. 57–63, 2004.
[14]
Y. Nishioka, Y. Horita, M. Tadokoro et al., “Mizoribine induces remission of relapsed ANCA-associated renal vasculitis,” Nephrology Dialysis Transplantation, vol. 21, no. 4, pp. 1087–1088, 2006.
[15]
A. L. Cheng, C. A. Hsiung, I. J. Su et al., “Steroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma,” Hepatology, vol. 37, no. 6, pp. 1320–1328, 2003.
[16]
A. S. F. Lok and B. J. McMahon, “Chronic hepatitis B,” Hepatology, vol. 45, no. 2, pp. 507–539, 2007.
[17]
K. Yoshioka, Y. Ohashi, T. Sakai et al., “A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome,” Kidney International, vol. 58, no. 1, pp. 317–324, 2000.
[18]
K. Kaneko, “Mizoribine for childhood IgA nephropathy,” Nephron, vol. 83, no. 4, pp. 376–377, 1999.
[19]
K. Hirayama, M. Kobayashi, Y. Hashimoto et al., “Treatment with the purine synthesis inhibitor mizoribine for ANCA-associated renal vasculitis,” American Journal of Kidney Diseases, vol. 44, no. 1, pp. 57–63, 2004.
[20]
T. Kuramoto, T. Daikoku, Y. Yoshida et al., “Novel anticytomegalovirus activity of immunosuppressant mizoribine and its synergism with ganciclovir,” Journal of Pharmacology and Experimental Therapeutics, vol. 333, no. 3, pp. 816–821, 2010.
