- Email: [email protected]
Mycophenolate mofetil - a new treatment for autoimmune hepatitis?
Journd of Hepotolog~~2000;33:480481 Prrnted in Denmark A// rzghts reserved Munksgaard Col,enhagm
Editorial
- a new treatment for autoimmune hepatitis?
Mycophenolate mofetil Anil
Dhawan
and Giorgina
See Article,
R
from the first descriptions of a chronic form of hepatitis, affecting mainly women and characterised by high serum gamma globulin and portal tract plasma cell infiltration, a dramatic response to corticosteroid therapy was observed (1,2). Ever since, steroids, with the addition of azathioprine as steroid sparing agent, have remained the mainstays for the treatment of autoimmune hepatitis (3-6). In an attempt to avoid side effects associated with the prolonged use of these drugs, trials have been conducted to withdraw one or both in a controlled manner. Hegarty et al. (7) reported an 87% relapse rate in 30 patients within 1 year of stopping both drugs compared to 48% and 15% relapse rates in similar studies from the Mayo Clinic (8) and the Royal Free Hospital (9), respectively. This discrepancy is possibly due to the stricter inclusion criteria in terms of duration of illness, antibody positivity and severity of changes on liver biopsy in the King’s College series (7). In a prospective lo-year follow up study, Johnson et al. (10) were able to stop steroids successfully in 60 out of 72 (83%) patients who were tolerating high-dose azathioprine maintenance (2 mg/ kg/day) with only minor side effects. For those patients who relapse on monotherapy with azathioprine, or show serious side effects to prednisolone and azathioprine, or are poorly compliant because of the cosmetic side effects of prednisolone, alternative treatments have been proposed. These include cyclosporin (11,12), tacrolimus (13) 6-mercaptopurine (14) and cyclophosphamide (15) all immunosuppressive agents that have potentially more serious side effects than prednisolone and azathioprine. Richardson et al., in this issue of Journal ofHepatology, report their experience with the use of mycophenolate mofetil (MMF) for the maintenIGHT
Correspondence: Anil Dhawan, Consultant Paediatric Hepatologist, Department of Child Health, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. Tel: 44 207 346 3214. Fax: 44 207 346 4224. e-mail: [email protected] 480
pages
Mieli-Vergani
371-375
ante of remission in seven patients with autoimmune hepatitis who were resistant to or intolerant of azathioprine (16). In this small series, the results were dramatic, with a significant decrease of disease activity at both the biochemical (five patients already had normal transaminase levels 3 months after starting MMF) and the histological level. The overall steroid requirement fell significantly and six patients were able to stop steroid treatment within 16 months. No major side effects were noted, only one patient requiring a dose reduction because of a fall in white cell count. MMF is the morpholinoethyl ester of mycophenolic acid (MPA) and is rapidly converted into MPA after oral absorption. MPA, a fermentation product of several Penicilliwn species, was first described by Gosio in 1896 (17), but failed to gain much clinical significance as an antimicrobial. In the early 1980’s, the observation that genetic defects of adenosine deaminase are associated with immunodeficiency, led to a renewed interest in the pharmacological activity of MPA, which inhibits & nova purine nucleotide synthesis by noncompetitively and irreversibly inhibiting inosine monophosphate dehydrogenase, thereby arresting DNA replication in T and B lymphocytes that are unable to use alternative salvage pathways ( 1819). In 1989, MMF was shown to prolong the survival of the graft in an experimental heterotopic heart transplantation model (20). The first human study was conducted in patients with severe rheumatoid arthritis unresponsive to cyclooxygenase inhibitors, methotrexate and long-acting anti-rheumatic drugs. MMF at the dose of l--1.5 g twice a day achieved prolonged remission in two-thirds of these patients without significant side effects (21). The first controlled trials of MMF as an anti-rejection agent in kidney transplant were performed in the early 1990s. In several multicentre, randomised, placebocontrolled trials comparing MMF with either placebo or azathioprine in combination with cyclosporin and prednisolone, the incidence of acute rejection in the MMF-treated patients was significantly lower when
Mycophenolate mofetil
compared to the other treatment groups (22-24). MMF was also shown to be effective in managing resistant rejection in liver and heart transplant recipients (25,26). In vitro, MMF appears to have a protective effect against Epstein-Barr virus (EBV)-related lymphoma by inhibiting the proliferation of EBV-infected B cells, while allowing T cell surveillance against tumour cells (27). However, at the 3rd year follow up of the Tricontinental Mycophenolate Mofetil Renal Transplantation Study, the same proportion of patients on MMF or azathioprine developed lymphoma (2/171 and l/162, respectively) (24). MMF has all the theoretical attributes for being a successful drug in the management of autoimmune hepatitis: though probably more powerful, it has a mechanism of action similar to that of azathioprine, a drug with a proven efficacy in this condition; it appears to be tolerated also by patients who do not tolerate azathioprine; it is not nephrotoxic or neurotoxic like tacrolimus or cyclosporin, nor does it have the serious side effects of cyclophosphamide. However, in the transplant setting, the use of MMF is associated with a marginally higher incidence of gastrointestinal (diarrhoea and vomiting) and haematological adverse events and a slightly higher incidence of infection when compared to azathioprine (22-24). The study of Richardson et al. (16) shows that MMF is an effective alternative in the treatment of autoimmune hepatitis in patients who are resistant or intolerant to azathioprine. Large and controlled studies using azathioprine versus MMF, in combination with steroids, as primary immunosuppressive agents, aimed at assessing efficacy and toxicity, are needed before a change in the current practice is warranted.
8.
9.
10.
Il.
12.
13.
14.
15.
16.
11. 18.
19. 20.
21.
22.
References 1. Page AR, Good RA. Plasma cell hepatitis with special attention to steroid therapy. Am J Dis Child 1960; 99: 2888314. 2. Effect of prednisone on the survival of patients with cirrhosis of the liver. A report from the Copenhagen Study Group for Liver Diseases. Lancet 1969; i: 119-21. trial of 3. Murray Lyon IM, Stern RB, Williams R. Controlled prednisolone and azathioprine in active chronic hepatitis. Lancet 1913; 2: 13551. 4. Mackay IR, Wood TJ. Lupoid hepatitis: a comparison of 22 cases with other types of liver disease. Q J Med 1962; 31: 485% 501. prospective trial 5. Cook GC, Mulligan R, Sherlock S. Controlled of corticosteroid therapy in active chronic hepatitis. Q J Med 1911; 40: 159-85. WHJ, Baggenstoss AH, Geall MG, 6. Soloway RD, Summerskill Gitnick GL, Elveback LR, et al. Clinical, biochemical and histological remission of severe chronic active liver disease: a controlled study of treatment and early prognosis. Gastroenterology 1912; 63: 820-33. I. Hegarty JE, Nouri Aria KT, Portmann B, Eddleston ALWF, Williams R. Relapse following treatment withdrawal in patients with
23.
24.
25.
26.
27.
autoimmune chronic active hepatitis. Hepatology 1983; 3: 685-9. Czaja AJ, Ludwig J, Baggenstoss AH, Wolf A. Corticosteroidtreated chronic active hepatitis in remission: uncertain prognosis of chronic persistent hepatitis. N Engl J Med 1981; 304: 5-9. Kirk AP Jain S, Pocock S, Thomas HC, Sherlock S. Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis. Gut 1980; 21: 78-83. Johnson PJ, McFarlane IG, Williams R. Azathioprine for longterm maintenance of remission in autoimmune hepatitis. N Engl J Med 1995; 333: 958863. Hyams JS, Ballow M, Leichtner AM. Cyclosporine treatment of autoimmune chronic active hepatitis. Gastroenterology 1981; 93: 890-3. Sherman KE, Narkewicz M, Pinto PC. Cyclosporine in the management of corticosteroid-resistant type I autoimmune chronic active hepatitis. J Hepatol 1994; 21: 104@7. Van Thiel DH, Wright H, Carroll P Abu-Elmagd K, RodriguezRilo H, McMichael J, et al. Tacrolimus: a potential new treatment for autoimmune chronic hepatitis: results of an open-label preliminary trial. Am J Gastroenterology 1995; 90: 1116. Pratt DS, Flavin DP Kaplan MM. The successful treatment of autoimmune hepatitis with 6-mercaptopurine after failure with azathioprine. Gastroenterology 1996; 110: 2114. Kanzler S, Gerken C, Dienes HP, Meyer zum Btischenfelde KH, Lohse AW. Cyclosphosphamide as alternative immunosuppression therapy for autoimmune hepatitis - report of three cases. Z Gastroenterol 1997; 35: 571-8. Richardson PD, James PD, Ryder SD. Mycophenolate mofetil for maintenance of remission in autoimmune hepatitis in patients resistant to or intolerant of azathioprine. J Hepatol 2000; 33: 371-5. Gosio B. Ricerche batteriologiche e chimiche sulle alterazoni de1 mais. Rivista d’Igiene e Sanita’ Pubblica Ann 1896; I: 825-68. Allison AC, Eugui EM. Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil. Immunol Rev 1993;136:5-28. Gummert JF, Ikonen T, Morris RE. Newer immunosuppressive drugs: a review. J Am Sot Nephrol 1999; 10: 136680. Morris RE, Hoyt EG, Eugui EM, Allison AC. Prolongation of rat heart allograft survival by RS-61443. Surg Forum 1989; 40: 337-8. Schiff MH, Goldblum R, Rees MMC. 2-Morpholino-ethyl mycophenolic acid (ME-MPA) in the treatment of refractory rheumatoid arthritis (RA). Arthr Rheum 1990; 33: S155. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. US Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1995; 60: 225-32. European Mycophenolate Mofetil Cooperative Study Group: placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection Lancet 1995; 345: 1321-5. Matthew TH. A blinded, long-term randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation. Results at three years. Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation 1998; 65: 145&4. Eckhoff DE, McGuire BM, Frenette LR, Contreras JL, Hudson SL, Bynon SJ. Tacrolimus (FK506) and mycophenolate mofetil combination therapy versus tacrolimus in adult liver transplantation. Transplantation 1998; 65: 18&l. Kobashigawa J, Miller L, Renlund D, Mentzer R, Alderman E, Bourge R, et al. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Transplantation 1998; 66: 501-15. Alfieri C, Allison AcC Kieff E. Effect of mycophenolic acid on Epstein-Barr virus infection of human B lymphocytes. Antimicrob Agents Chemother 1994; 38: 126.
481
Editorial
- a new treatment for autoimmune hepatitis?
Mycophenolate mofetil Anil
Dhawan
and Giorgina
See Article,
R
from the first descriptions of a chronic form of hepatitis, affecting mainly women and characterised by high serum gamma globulin and portal tract plasma cell infiltration, a dramatic response to corticosteroid therapy was observed (1,2). Ever since, steroids, with the addition of azathioprine as steroid sparing agent, have remained the mainstays for the treatment of autoimmune hepatitis (3-6). In an attempt to avoid side effects associated with the prolonged use of these drugs, trials have been conducted to withdraw one or both in a controlled manner. Hegarty et al. (7) reported an 87% relapse rate in 30 patients within 1 year of stopping both drugs compared to 48% and 15% relapse rates in similar studies from the Mayo Clinic (8) and the Royal Free Hospital (9), respectively. This discrepancy is possibly due to the stricter inclusion criteria in terms of duration of illness, antibody positivity and severity of changes on liver biopsy in the King’s College series (7). In a prospective lo-year follow up study, Johnson et al. (10) were able to stop steroids successfully in 60 out of 72 (83%) patients who were tolerating high-dose azathioprine maintenance (2 mg/ kg/day) with only minor side effects. For those patients who relapse on monotherapy with azathioprine, or show serious side effects to prednisolone and azathioprine, or are poorly compliant because of the cosmetic side effects of prednisolone, alternative treatments have been proposed. These include cyclosporin (11,12), tacrolimus (13) 6-mercaptopurine (14) and cyclophosphamide (15) all immunosuppressive agents that have potentially more serious side effects than prednisolone and azathioprine. Richardson et al., in this issue of Journal ofHepatology, report their experience with the use of mycophenolate mofetil (MMF) for the maintenIGHT
Correspondence: Anil Dhawan, Consultant Paediatric Hepatologist, Department of Child Health, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. Tel: 44 207 346 3214. Fax: 44 207 346 4224. e-mail: [email protected] 480
pages
Mieli-Vergani
371-375
ante of remission in seven patients with autoimmune hepatitis who were resistant to or intolerant of azathioprine (16). In this small series, the results were dramatic, with a significant decrease of disease activity at both the biochemical (five patients already had normal transaminase levels 3 months after starting MMF) and the histological level. The overall steroid requirement fell significantly and six patients were able to stop steroid treatment within 16 months. No major side effects were noted, only one patient requiring a dose reduction because of a fall in white cell count. MMF is the morpholinoethyl ester of mycophenolic acid (MPA) and is rapidly converted into MPA after oral absorption. MPA, a fermentation product of several Penicilliwn species, was first described by Gosio in 1896 (17), but failed to gain much clinical significance as an antimicrobial. In the early 1980’s, the observation that genetic defects of adenosine deaminase are associated with immunodeficiency, led to a renewed interest in the pharmacological activity of MPA, which inhibits & nova purine nucleotide synthesis by noncompetitively and irreversibly inhibiting inosine monophosphate dehydrogenase, thereby arresting DNA replication in T and B lymphocytes that are unable to use alternative salvage pathways ( 1819). In 1989, MMF was shown to prolong the survival of the graft in an experimental heterotopic heart transplantation model (20). The first human study was conducted in patients with severe rheumatoid arthritis unresponsive to cyclooxygenase inhibitors, methotrexate and long-acting anti-rheumatic drugs. MMF at the dose of l--1.5 g twice a day achieved prolonged remission in two-thirds of these patients without significant side effects (21). The first controlled trials of MMF as an anti-rejection agent in kidney transplant were performed in the early 1990s. In several multicentre, randomised, placebocontrolled trials comparing MMF with either placebo or azathioprine in combination with cyclosporin and prednisolone, the incidence of acute rejection in the MMF-treated patients was significantly lower when
Mycophenolate mofetil
compared to the other treatment groups (22-24). MMF was also shown to be effective in managing resistant rejection in liver and heart transplant recipients (25,26). In vitro, MMF appears to have a protective effect against Epstein-Barr virus (EBV)-related lymphoma by inhibiting the proliferation of EBV-infected B cells, while allowing T cell surveillance against tumour cells (27). However, at the 3rd year follow up of the Tricontinental Mycophenolate Mofetil Renal Transplantation Study, the same proportion of patients on MMF or azathioprine developed lymphoma (2/171 and l/162, respectively) (24). MMF has all the theoretical attributes for being a successful drug in the management of autoimmune hepatitis: though probably more powerful, it has a mechanism of action similar to that of azathioprine, a drug with a proven efficacy in this condition; it appears to be tolerated also by patients who do not tolerate azathioprine; it is not nephrotoxic or neurotoxic like tacrolimus or cyclosporin, nor does it have the serious side effects of cyclophosphamide. However, in the transplant setting, the use of MMF is associated with a marginally higher incidence of gastrointestinal (diarrhoea and vomiting) and haematological adverse events and a slightly higher incidence of infection when compared to azathioprine (22-24). The study of Richardson et al. (16) shows that MMF is an effective alternative in the treatment of autoimmune hepatitis in patients who are resistant or intolerant to azathioprine. Large and controlled studies using azathioprine versus MMF, in combination with steroids, as primary immunosuppressive agents, aimed at assessing efficacy and toxicity, are needed before a change in the current practice is warranted.
8.
9.
10.
Il.
12.
13.
14.
15.
16.
11. 18.
19. 20.
21.
22.
References 1. Page AR, Good RA. Plasma cell hepatitis with special attention to steroid therapy. Am J Dis Child 1960; 99: 2888314. 2. Effect of prednisone on the survival of patients with cirrhosis of the liver. A report from the Copenhagen Study Group for Liver Diseases. Lancet 1969; i: 119-21. trial of 3. Murray Lyon IM, Stern RB, Williams R. Controlled prednisolone and azathioprine in active chronic hepatitis. Lancet 1913; 2: 13551. 4. Mackay IR, Wood TJ. Lupoid hepatitis: a comparison of 22 cases with other types of liver disease. Q J Med 1962; 31: 485% 501. prospective trial 5. Cook GC, Mulligan R, Sherlock S. Controlled of corticosteroid therapy in active chronic hepatitis. Q J Med 1911; 40: 159-85. WHJ, Baggenstoss AH, Geall MG, 6. Soloway RD, Summerskill Gitnick GL, Elveback LR, et al. Clinical, biochemical and histological remission of severe chronic active liver disease: a controlled study of treatment and early prognosis. Gastroenterology 1912; 63: 820-33. I. Hegarty JE, Nouri Aria KT, Portmann B, Eddleston ALWF, Williams R. Relapse following treatment withdrawal in patients with
23.
24.
25.
26.
27.
autoimmune chronic active hepatitis. Hepatology 1983; 3: 685-9. Czaja AJ, Ludwig J, Baggenstoss AH, Wolf A. Corticosteroidtreated chronic active hepatitis in remission: uncertain prognosis of chronic persistent hepatitis. N Engl J Med 1981; 304: 5-9. Kirk AP Jain S, Pocock S, Thomas HC, Sherlock S. Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis. Gut 1980; 21: 78-83. Johnson PJ, McFarlane IG, Williams R. Azathioprine for longterm maintenance of remission in autoimmune hepatitis. N Engl J Med 1995; 333: 958863. Hyams JS, Ballow M, Leichtner AM. Cyclosporine treatment of autoimmune chronic active hepatitis. Gastroenterology 1981; 93: 890-3. Sherman KE, Narkewicz M, Pinto PC. Cyclosporine in the management of corticosteroid-resistant type I autoimmune chronic active hepatitis. J Hepatol 1994; 21: 104@7. Van Thiel DH, Wright H, Carroll P Abu-Elmagd K, RodriguezRilo H, McMichael J, et al. Tacrolimus: a potential new treatment for autoimmune chronic hepatitis: results of an open-label preliminary trial. Am J Gastroenterology 1995; 90: 1116. Pratt DS, Flavin DP Kaplan MM. The successful treatment of autoimmune hepatitis with 6-mercaptopurine after failure with azathioprine. Gastroenterology 1996; 110: 2114. Kanzler S, Gerken C, Dienes HP, Meyer zum Btischenfelde KH, Lohse AW. Cyclosphosphamide as alternative immunosuppression therapy for autoimmune hepatitis - report of three cases. Z Gastroenterol 1997; 35: 571-8. Richardson PD, James PD, Ryder SD. Mycophenolate mofetil for maintenance of remission in autoimmune hepatitis in patients resistant to or intolerant of azathioprine. J Hepatol 2000; 33: 371-5. Gosio B. Ricerche batteriologiche e chimiche sulle alterazoni de1 mais. Rivista d’Igiene e Sanita’ Pubblica Ann 1896; I: 825-68. Allison AC, Eugui EM. Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil. Immunol Rev 1993;136:5-28. Gummert JF, Ikonen T, Morris RE. Newer immunosuppressive drugs: a review. J Am Sot Nephrol 1999; 10: 136680. Morris RE, Hoyt EG, Eugui EM, Allison AC. Prolongation of rat heart allograft survival by RS-61443. Surg Forum 1989; 40: 337-8. Schiff MH, Goldblum R, Rees MMC. 2-Morpholino-ethyl mycophenolic acid (ME-MPA) in the treatment of refractory rheumatoid arthritis (RA). Arthr Rheum 1990; 33: S155. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. US Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1995; 60: 225-32. European Mycophenolate Mofetil Cooperative Study Group: placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection Lancet 1995; 345: 1321-5. Matthew TH. A blinded, long-term randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation. Results at three years. Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation 1998; 65: 145&4. Eckhoff DE, McGuire BM, Frenette LR, Contreras JL, Hudson SL, Bynon SJ. Tacrolimus (FK506) and mycophenolate mofetil combination therapy versus tacrolimus in adult liver transplantation. Transplantation 1998; 65: 18&l. Kobashigawa J, Miller L, Renlund D, Mentzer R, Alderman E, Bourge R, et al. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Transplantation 1998; 66: 501-15. Alfieri C, Allison AcC Kieff E. Effect of mycophenolic acid on Epstein-Barr virus infection of human B lymphocytes. Antimicrob Agents Chemother 1994; 38: 126.
481