- Email: [email protected]
Methotrexate for primary biliary cirrhosis
1824
CORRESPONDENCE
2. Parkinson A, Hurwitz A. Omeprazole and the induction of human cytochrome P-450: a response to concerns about potential adverse effects. Gastroenterology 1991;1001157-1164. 3. Moldeus PA, Berlin RG, Lu A, Castagnoli N, Carlsson E, Andersson T. P450/Losec. Gastroenterology 1991;100:14881489. 4. Whitlock JP. Genetic and molecular aspects of 2,3,7,8-tetrachlorodibenzo-p-dioxin action. Annu Rev Pharmacol Toxic01 1990;30:251-277. 5. Poland A, Knutson JC. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: Examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol 1982;22:517-554. 6. Lucier GW. Receptor-mediated carcinogenesis. In: Vainio H, ed. Approaches for classifying carcinogens according to mechanism. IARC Scientific Publication Series, 1991 (in press). 7. Lin FH, Clark G, Birnbaum LS, Lucier GW, Goldstein JA. Influence of the Ah locus on the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the hepatic epidermal growth factor receptor. Mol Pharmacol 1991;39:307-313. 8. Bombick DW, Jankun J, Tullis K, Matsumura F. 2,3,7,8-Tetrachlorodibenzo-p-dioxin causes increases in c-erb-A and levels of protein kinases in selected tissues of responsive mouse strains. Proc Nat1 Acad Sci USA 1988;85:4128-4132. 9. Romkes M, Piskorska-Pliszczynska J, Safe S. Effects of 2,3,7,8tetrachlorodibenzo-p-dioxin on hepatic and uterine estrogen receptor levels in rats. Toxic01 Appl Pharmacol 1987;87:306314. 10. Sunahara GI, Lucier GW, McCoy Z, Bresnick EM, Sanchez ER, Nelson KG. Characterization of 2,3,7,8-tetrachlorodibenzo-pdioxin-mediated decreases in dexamethasone binding to rat hepatic cytosolic glucocorticoid receptor. Mol Pharmacol 1987;32:239-247. 11. Clark GC, Taylor MJ, Tritscher AM, Lucier GW. Tumor necrosis factor involvement in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) mediated endotoxin hypersensitivity in C57B1/6J mice congenic at the Ah locus. Toxic01 Appl Pharmacoll991 (in press). 12. Sutter TR, Guzman K, Dold KM, Greenlee WF. Human gene targets for dioxin include plasminogen activator inhibitor-2 and interleukin-18. Science 1991 (in press). 13. Sibergeld EK, Gasiewicz TA. Dioxins and the Ah receptor. Am J Ind Med 1989;16:455-474. 14. Mabley TA, Theobald HM, Ingall GB, Peterson RE. Hypergastrinemia is associated with decreased gastric acid secretion in 2,3,7,8-tetrachlorodibenzo-p-dioxin treated rats. Toxic01 Appl Pharmacol1990;106:518-528. 15. Ryberg B, Tielemans Y, Axelson J, Carlsson E, Hakanson R, Mattsson H, Sundler F, Willems G. Gastrin stimulates the selfreplication rate of enterochromaffinlike cells in the rat stomach. Effects of omeprazole, ranitidine and gastrin-17 in intact and antrectomized rats. Gastroenterology 1990;99:935-942. 16. Ekman L, Hansson E, Havu N, Carlsson E, Lundberg C. Toxicological studies on omeprazole. Stand J Gastroenterol 1985;2O(Suppl 108):53-69.
Methotrexate
GASTROENTEROLOGY Vol. 102, No. 5
one patient with PSC treated for 12 years and 3 g in several patients with PSC and PBC. Furthermore, bone marrow suppression is rare. However, reversible but potentially life-threatening interstitial pneumonitis (called alveolitis in the editorial) is a problem in PBC but much less so in PSC. We advise our patients to abstain from alcohol consumption and, as pointed out in the editorial, to practice birth control while on methotrexate therapy. We are pleased that the authors of the editorial performed a similar short-term trial of methotrexate in 9 PBC patients and confirmed our results.’ Because of our initial results, we embarked on a long-term double-blind trial of methotrexate vs. colchicine in 89 patients with PBC 3 years ago. Thus far, we have observed no hepatotoxicity and gratifying improvement in many patients. However, reversible interstitial pneumonitis has occurred in 10% of patients who received methotrexate. Although we do not have sufficient long-term data on the potential hepatotoxicity of methotrexate in PBC, we strongly believe that our initial positive results are so encouraging that vigorously controlled studies, as suggested in the editorial, should be performed. We are also encouraged by the fact that recent experience with methotrexate treatment in rheumatoid arthritis suggests that the incidence of methotrexate-induced liver disease is much less than previously reported.+’ We would also like to emphasize that the long-term consequences of untreated PBC are serious and usually result in liver failure and the need for liver transplantation Thus, we believe that the potential toxicity of methotrexate, although real, is not sufficient to discourage its use under properly controlled conditions. MARSHALL M. KAPLAN, M.D. TAMSIN A. KNOX, M.D.
Gastroenterology Service New England Medical Center Hospitals 750 Washington Street Boston, Massachusetts 02111 1.
1991;101:1440-1442. 2. Kaplan MM, Arora S, Pincus SH: Primary sclerosing
cholangitis and low-dose oral pulse methotrexate therapy. Clinical and histologic response. Ann Intern Med 1987;106:231-235. 3. Kaplan MM, Knox T, Arora S: Primary biliary cirrhosis treated with low-dose oral pulse methotrexate. Ann Intern Med 1988;109:429-431. 4. Bergasa NV, Hoofnagle JH, Axiotis CA, Rabin L, Park Y, Jones EA: Oral methotrexate (MTX) for primary biliary cirrhosis (PBC): preliminary report (abstr). Gastroenterology 1991;100: A720. 5. Zachariae 6. 7.
8.
for Primary Biliary Cirrhosis
Dear Sir: We share similar concerns about the potential hepatotoxicity of methotrexate expressed in the editorial of Hoofnagle and Bergasa.l Because of these concerns, we initially monitored patients with monthly blood tests and biannual liver biopsies when we treated our first patient with primary sclerosing cholangitis (PSC) with methotrexate in 1979* and our first patient with primary biliary cirrhosis (PBC) in 1986.3 Thus far, we have observed no hepatotoxicity in any patient treated with low-dose methotrexate. The cumulative methotrexate dose has now exceeded 10 gin
Hoofnagle JH, Bergasa NV. Methotrexate therapy of primary biliary cirrhosis: promising but worrisome. Gastroenterology
9.
H, Sogaard H: Methotrexate-induced liver cirrhosis: a follow-up. Dermatologica 1987;175:178-182. Mackenzie AH: Hepatotoxicity ofprolonged methotrexate therapy for rheumatoid arthritis. Cleve Clin Q 1985;52:129-135. Rau R, Karger T, Herborn G, Frenzel H: Liver biopsy findings in patients with rheumatoid arthritis undergoing longterm treatment with methotrexate. J Rheumatol 1989;16:489-493. Bjorkman DJ, Boschert ME, Tolman KG, Clegg D, Ward JR: Serum procollagenpeptide levels in chronic methotrexate therapy for rheumatoid arthritis. Hepatology 1991;14:269A. Kaplan MM. Methotrexate hepatotoxicity and the premature reporting of Mark Twain’s death: both greatly exaggerated. Hepatology 1990;12:784-786.
Beer and Release of Gastrin in Humans Dear Sir: With great interest we have read the paper by Singer et al.’ on the effect of (non-)alcoholic ingredients of beer and of some of its preproducts on the release of gastrin and gastric acid secretion.
CORRESPONDENCE
2. Parkinson A, Hurwitz A. Omeprazole and the induction of human cytochrome P-450: a response to concerns about potential adverse effects. Gastroenterology 1991;1001157-1164. 3. Moldeus PA, Berlin RG, Lu A, Castagnoli N, Carlsson E, Andersson T. P450/Losec. Gastroenterology 1991;100:14881489. 4. Whitlock JP. Genetic and molecular aspects of 2,3,7,8-tetrachlorodibenzo-p-dioxin action. Annu Rev Pharmacol Toxic01 1990;30:251-277. 5. Poland A, Knutson JC. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: Examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol 1982;22:517-554. 6. Lucier GW. Receptor-mediated carcinogenesis. In: Vainio H, ed. Approaches for classifying carcinogens according to mechanism. IARC Scientific Publication Series, 1991 (in press). 7. Lin FH, Clark G, Birnbaum LS, Lucier GW, Goldstein JA. Influence of the Ah locus on the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the hepatic epidermal growth factor receptor. Mol Pharmacol 1991;39:307-313. 8. Bombick DW, Jankun J, Tullis K, Matsumura F. 2,3,7,8-Tetrachlorodibenzo-p-dioxin causes increases in c-erb-A and levels of protein kinases in selected tissues of responsive mouse strains. Proc Nat1 Acad Sci USA 1988;85:4128-4132. 9. Romkes M, Piskorska-Pliszczynska J, Safe S. Effects of 2,3,7,8tetrachlorodibenzo-p-dioxin on hepatic and uterine estrogen receptor levels in rats. Toxic01 Appl Pharmacol 1987;87:306314. 10. Sunahara GI, Lucier GW, McCoy Z, Bresnick EM, Sanchez ER, Nelson KG. Characterization of 2,3,7,8-tetrachlorodibenzo-pdioxin-mediated decreases in dexamethasone binding to rat hepatic cytosolic glucocorticoid receptor. Mol Pharmacol 1987;32:239-247. 11. Clark GC, Taylor MJ, Tritscher AM, Lucier GW. Tumor necrosis factor involvement in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) mediated endotoxin hypersensitivity in C57B1/6J mice congenic at the Ah locus. Toxic01 Appl Pharmacoll991 (in press). 12. Sutter TR, Guzman K, Dold KM, Greenlee WF. Human gene targets for dioxin include plasminogen activator inhibitor-2 and interleukin-18. Science 1991 (in press). 13. Sibergeld EK, Gasiewicz TA. Dioxins and the Ah receptor. Am J Ind Med 1989;16:455-474. 14. Mabley TA, Theobald HM, Ingall GB, Peterson RE. Hypergastrinemia is associated with decreased gastric acid secretion in 2,3,7,8-tetrachlorodibenzo-p-dioxin treated rats. Toxic01 Appl Pharmacol1990;106:518-528. 15. Ryberg B, Tielemans Y, Axelson J, Carlsson E, Hakanson R, Mattsson H, Sundler F, Willems G. Gastrin stimulates the selfreplication rate of enterochromaffinlike cells in the rat stomach. Effects of omeprazole, ranitidine and gastrin-17 in intact and antrectomized rats. Gastroenterology 1990;99:935-942. 16. Ekman L, Hansson E, Havu N, Carlsson E, Lundberg C. Toxicological studies on omeprazole. Stand J Gastroenterol 1985;2O(Suppl 108):53-69.
Methotrexate
GASTROENTEROLOGY Vol. 102, No. 5
one patient with PSC treated for 12 years and 3 g in several patients with PSC and PBC. Furthermore, bone marrow suppression is rare. However, reversible but potentially life-threatening interstitial pneumonitis (called alveolitis in the editorial) is a problem in PBC but much less so in PSC. We advise our patients to abstain from alcohol consumption and, as pointed out in the editorial, to practice birth control while on methotrexate therapy. We are pleased that the authors of the editorial performed a similar short-term trial of methotrexate in 9 PBC patients and confirmed our results.’ Because of our initial results, we embarked on a long-term double-blind trial of methotrexate vs. colchicine in 89 patients with PBC 3 years ago. Thus far, we have observed no hepatotoxicity and gratifying improvement in many patients. However, reversible interstitial pneumonitis has occurred in 10% of patients who received methotrexate. Although we do not have sufficient long-term data on the potential hepatotoxicity of methotrexate in PBC, we strongly believe that our initial positive results are so encouraging that vigorously controlled studies, as suggested in the editorial, should be performed. We are also encouraged by the fact that recent experience with methotrexate treatment in rheumatoid arthritis suggests that the incidence of methotrexate-induced liver disease is much less than previously reported.+’ We would also like to emphasize that the long-term consequences of untreated PBC are serious and usually result in liver failure and the need for liver transplantation Thus, we believe that the potential toxicity of methotrexate, although real, is not sufficient to discourage its use under properly controlled conditions. MARSHALL M. KAPLAN, M.D. TAMSIN A. KNOX, M.D.
Gastroenterology Service New England Medical Center Hospitals 750 Washington Street Boston, Massachusetts 02111 1.
1991;101:1440-1442. 2. Kaplan MM, Arora S, Pincus SH: Primary sclerosing
cholangitis and low-dose oral pulse methotrexate therapy. Clinical and histologic response. Ann Intern Med 1987;106:231-235. 3. Kaplan MM, Knox T, Arora S: Primary biliary cirrhosis treated with low-dose oral pulse methotrexate. Ann Intern Med 1988;109:429-431. 4. Bergasa NV, Hoofnagle JH, Axiotis CA, Rabin L, Park Y, Jones EA: Oral methotrexate (MTX) for primary biliary cirrhosis (PBC): preliminary report (abstr). Gastroenterology 1991;100: A720. 5. Zachariae 6. 7.
8.
for Primary Biliary Cirrhosis
Dear Sir: We share similar concerns about the potential hepatotoxicity of methotrexate expressed in the editorial of Hoofnagle and Bergasa.l Because of these concerns, we initially monitored patients with monthly blood tests and biannual liver biopsies when we treated our first patient with primary sclerosing cholangitis (PSC) with methotrexate in 1979* and our first patient with primary biliary cirrhosis (PBC) in 1986.3 Thus far, we have observed no hepatotoxicity in any patient treated with low-dose methotrexate. The cumulative methotrexate dose has now exceeded 10 gin
Hoofnagle JH, Bergasa NV. Methotrexate therapy of primary biliary cirrhosis: promising but worrisome. Gastroenterology
9.
H, Sogaard H: Methotrexate-induced liver cirrhosis: a follow-up. Dermatologica 1987;175:178-182. Mackenzie AH: Hepatotoxicity ofprolonged methotrexate therapy for rheumatoid arthritis. Cleve Clin Q 1985;52:129-135. Rau R, Karger T, Herborn G, Frenzel H: Liver biopsy findings in patients with rheumatoid arthritis undergoing longterm treatment with methotrexate. J Rheumatol 1989;16:489-493. Bjorkman DJ, Boschert ME, Tolman KG, Clegg D, Ward JR: Serum procollagenpeptide levels in chronic methotrexate therapy for rheumatoid arthritis. Hepatology 1991;14:269A. Kaplan MM. Methotrexate hepatotoxicity and the premature reporting of Mark Twain’s death: both greatly exaggerated. Hepatology 1990;12:784-786.
Beer and Release of Gastrin in Humans Dear Sir: With great interest we have read the paper by Singer et al.’ on the effect of (non-)alcoholic ingredients of beer and of some of its preproducts on the release of gastrin and gastric acid secretion.