Advertisement

Digestive Diseases and Sciences

, Volume 55, Issue 11, pp 3207–3217 | Cite as

Methotrexate in Patients with Primary Biliary Cirrhosis Who Respond Incompletely to Treatment With Ursodeoxycholic Acid

  • Marshall M. KaplanEmail author
  • Alan Bonder
  • Robin Ruthazer
  • Peter A. L. Bonis
Original Article

Abstract

Background

Approximately 35% of PBC patients have progressive disease despite treatment with UDCA.

Aims

We offered treatment with methotrexate and colchicine to PBC patients who had not responded fully to UDCA, after at least 1 year of treatment.

Methods

A total of 91 PBC patients failed to respond adequately to UDCA, defined as patients whose liver biopsies showed persistent interface hepatitis and whose serum alkaline phosphatase levels remained more than 50% above normal after at least 12 months on UDCA. We added colchicine (0.6 mg orally twice daily) for 6 months. If there was no decrease in alkaline phosphatase, methotrexate (0.25 mg/kg lean body weight orally per week) was added. Liver biopsies were performed at least three times: at diagnosis, after a patient had been on UDCA for at least 1 year (mean 3.4 years), and after a patient had been on methotrexate for at least 6 months (mean 2.2 years). A fourth liver biopsy was performed in 51 patients after they had been on methotrexate for at least another year (mean 3.5 years).

Results

From the time that methotrexate was begun until the final visit, there were significant decreases in the mean levels of alkaline phosphatase, 323 to 151, ALT, 73 to 39, fibrosis, 2.5 to 2.0, and inflammation scores, 2.0 to 1.0, (p < 0.0001 for all). Based on pre-specified definitions, 73 patients (80%) responded to methotrexate while 18 (20%) did not.

Conclusions

In 91 PBC patients who responded incompletely to UDCA, colchicine and methotrexate significantly improved liver enzyme tests and liver histology.

Keywords

Primary biliary cirrhosis Unresponsive to ursodiol Response to methotrexate Colchicine 

Notes

Conflict of interest statement

None.

References

  1. 1.
    Lindor K, Gershwin M, Poupon R, Kaplan M, Bergasa N, Heathcote E. AASLD practice guidelines: primary Biliary Cirrhosis. Hepatology. 2009;50:291–308.CrossRefPubMedGoogle Scholar
  2. 2.
    Gong Y, Huang Z, Christensen E, Gluud C. Ursodeoxycholic acid for patients with primary biliary cirrhosis: an updated systemic review and meta-analysis of randomized clinical trials using Bayesian approach as sensitivity analysis. Am J Gastroenterol. 2007;102:1799–1807.CrossRefPubMedGoogle Scholar
  3. 3.
    Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology. 2006;130:715–720.CrossRefPubMedGoogle Scholar
  4. 4.
    Corpechot C, Abenavoli L, Rabahi N, Chrétien Y, Andréani T, Johanet C, Chazouillères O, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48:871–877.Google Scholar
  5. 5.
    Lee J, Belanger A, Friedman S, Bach N. Transplantation trends among primary biliary cirrhosis patients from 1995 to 2004. Hepatology. 2006;44:628A.Google Scholar
  6. 6.
    Kaplan M, Poupon R. Treatment with immunosupressives in patients with primary biliary cirrhosis who fail to respond to ursodiol. Hepatology. 2009;50:562.CrossRefGoogle Scholar
  7. 7.
    Kaplan MM, Knox TA, Arora SA. Primary biliary cirrhosis treated with low-dose oral pulse methotrexate. Ann Intern Med. 1988;109:429–431.PubMedGoogle Scholar
  8. 8.
    Kaplan M, DeLellis R, Wolfe H. Sustained biochemical and histological remission of primary biliary cirrhosis in response to medical treatment. Ann Intern Med. 1997;126:682–688.PubMedGoogle Scholar
  9. 9.
    Bonis PA, Kaplan MM. The effects of colchicine and methotrexate are additive to ursodeoxycholic acid for patients with primary biliary cirrhosis (PBC) who have responded incompletely to ursodeoxycholic acid. Hepatology. 1997;26:438A.CrossRefGoogle Scholar
  10. 10.
    Combes B, Emerson SS, Flye NL, et al. Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology. 2005;42:1184–1193.CrossRefPubMedGoogle Scholar
  11. 11.
    Hendrickse M, Rigney E, Giaffer M, et al. Low-dose methotrexate is ineffective in primary biliary cirrhosis: long-term results of a placebo-controlled trial. Gastroenterology. 1999;117:400–407.CrossRefPubMedGoogle Scholar
  12. 12.
    Kaplan MM, Cheng S, Price LL, Bonis PA. A randomized controlled trial of colchicine plus ursodiol versus methotrexate plus ursodiol in primary biliary cirrhosis: ten-year results. Hepatology. 2004;39:915–923.CrossRefPubMedGoogle Scholar
  13. 13.
    Gong Y, Gluud C. Methotrexate for primary biliary cirrhosis. Cochrane Database Syst Rev. 2005;Jul 20;(3):CD004385, PMID: 16034929.Google Scholar
  14. 14.
    Corpechot C, Carrat F, Poupon R, Poupon RE. Primary biliary cirrhosis: incidence and predictive factors of cirrhosis development in ursodiol-treated patients. Gastroenterology. 2002;122:652–658.CrossRefPubMedGoogle Scholar
  15. 15.
    Lindor K. Ursodeoxycholic acid for the treatment of primary biliary cirrhosis. N Engl J Med. 2007;357:1524–1529.CrossRefPubMedGoogle Scholar
  16. 16.
    Kaplan MM, Gershwin EM. Primary biliary cirrhosis. N Eng J Med. 2005;353:1261–1273.CrossRefGoogle Scholar
  17. 17.
    Goodman ZD, McNally PR, Davis DR, Ishak KG. Autoimmune cholangitis: a variant of primary biliary cirrhosis. Dig Dis Sci. 1995;40:1232–1242.CrossRefPubMedGoogle Scholar
  18. 18.
    Poupon R, Chazouilleres O, Corpechot C, Chretien Y. Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis. Hepatology. 2006;44:85–90.CrossRefPubMedGoogle Scholar
  19. 19.
    Kaplan M, Schmid C, McKusick A, Provenzale D, Sharma A, Sepe T. Double-blind trial of methotrexate (MTX) versus colchicine (COLCH) in primary biliary cirrhosis. Hepatology. 1993;18:176A.Google Scholar
  20. 20.
    Chazouilleres O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome; clinical features and response to therapy. Hepatology. 1998;28:296–301.CrossRefPubMedGoogle Scholar
  21. 21.
    Novak K, Swain MG. Role of methotrexate in the treatment of chronic cholestatic disorders. Clin Liver Dis. 2008;12:81–96. (viii).CrossRefPubMedGoogle Scholar
  22. 22.
    Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48:871–877.CrossRefPubMedGoogle Scholar
  23. 23.
    Babatin MA, Sanai FM, Swain MG. Methotrexate therapy for the symptomatic treatment of primary biliary cirrhosis patients, who are biochemical incomplete responders to ursodeoxycholic acid therapy. Aliment Pharmacol Ther. 2006;24:813–820.CrossRefPubMedGoogle Scholar
  24. 24.
    Bonis PAL, Kaplan M. Methotrexate in primary biliary cirrhosis unresponsive to ursodeoxycholic acid: an observational study in 10 patients. Gastroenterology. 1999;117:395–399.CrossRefPubMedGoogle Scholar
  25. 25.
    Bonis PA, Kaplan M. Methotrexate for treatment of primary biliary cirrhosis. Hepatology. 2006;43:632. (author reply 632–633).CrossRefPubMedGoogle Scholar
  26. 26.
    Nyfors A. Liver biopsies from psoriatics related to methotrexate therapy 3. Findings in post-methotrexate liver biopsies from 160 psoriatics. Acta Pathol Microbiol Scand A. 1977;85:511–518.PubMedGoogle Scholar
  27. 27.
    Roenigk HJ, Auerbach R, Maibach H, Weinstein G. Methotrexate guidelines–revised. J Am Acad Dermatol. 1982;6:145–155.CrossRefPubMedGoogle Scholar
  28. 28.
    Zachariae H, Kragballe K, Søgaard H. Methotrexate induced liver cirrhosis. Studies including serial liver biopsies during continued treatment. Br J Dermatol. 1980;102:407–412.CrossRefPubMedGoogle Scholar
  29. 29.
    Yazici Y, Erkan D, Harrison M, Nikolov N, Paget SA. Methotrexate use in rheumatoid arthritis is associated with few clinically significant liver function test abnormalities. Clin Exp Rheumatol. 2005;23:517–520.PubMedGoogle Scholar
  30. 30.
    Menter A, Korman N, Elmets C, Feldman S, Gelfand JM, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol. 2009;61:451–485.CrossRefPubMedGoogle Scholar
  31. 31.
    Saag K, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis J, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;15:762–784.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Marshall M. Kaplan
    • 1
    Email author
  • Alan Bonder
    • 1
  • Robin Ruthazer
    • 2
  • Peter A. L. Bonis
    • 1
    • 2
  1. 1.Division of GastroenterologyTufts Medical CenterBostonUSA
  2. 2.Institute for Clinical Research and Health Policy StudiesTufts Medical CenterBostonUSA

Personalised recommendations