Low-dose methotrexate in primary biliary cirrhosis

Low-dose methotrexate in primary biliary cirrhosis

1510 CORRESPONDENCE suggested that even small ‘‘acid pulses’’ might induce proliferation and decrease differentiation in tissue culture from patient...

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suggested that even small ‘‘acid pulses’’ might induce proliferation and decrease differentiation in tissue culture from patients with Barrett’s esophagus, we believe that the long-term goal of therapy would be to eliminate any acid exposure on this susceptible mucosa. Furthermore, studies from our laboratory indicate that this can be accomplished in most patients by combining a PPI for daytime acid with bedtime H2-receptor antagonists to control nocturnal acid.8 We believe that a regimen of this kind should be considered the preferred method of acid control in patients with Barrett’s. This conclusion is supported by our original observation showing that 80% of patients with Barrett’s esophagus having symptom resolution on PPI therapy continue to have abnormal nocturnal reflux.3 It is further supported by the study of Ouatu-Lascar et al. in which 14 of the 16 patients in group B (persistent pathological reflux) and even 3 of the 26 patients in group A (normalized intraesophageal pH) had abnormal levels of esophageal acid exposure while supine during the night. It would be interesting to know whether those patients had higher PCNA scores and lower villin expression than the other patients in group A. Will effective acid control over a long period lead to prevention of dysplasia or true regression in patients with Barrett’s esophagus? It is our hypothesis that this question will not be adequately answered until more effective acid control is used in long-term prospective studies involving these patients. DONALD O. CASTELL, M.D. DAVID A. KATZKA, M.D. Department of Medicine Graduate Hospital Philadelphia, Pennsylvania 1. Ouatu-Lascar R, Fitzgerald RC, Triadafilopoulos G. Differentiation and proliferation in Barrett’s esophagus and the effects of acid suppression. Gastroenterology 1999;117:327–335. 2. Fitzgerald RC, Omary MB, Triadafilopoulos G. Dynamic effects of acid on Barrett’s esophagus: an ex vivo proliferation and differentiation model. J Clin Invest 1996;98:2120–2128. 3. Katzka DA, Castell DO. Successful elimination of reflux symptoms does not ensure adequate control of acid reflux in Barrett’s esophagus. Am J Gastroenterol 1994;89:989–991. 4. Ouatu-Lascar R, Triadafilopoulos G. Complete elimination of reflux symptoms does not guarantee normalization of intraesophageal acid reflux in patients with Barrett’s esophagus. Am J Gastroenterol 1998;93:711–716. 5. Johnson D, Winters C, Spurling T, et al. Esophageal acid sensitivity in Barrett’s esophagus. J Clin Gastroenterol 1987;9:23–27. 6. Sharma P, Sampliner RE, Camargo E. Normalization of esophageal pH with high-dose proton pump inhibitor therapy does not result in regression of Barrett’s esophagus. Am J Gastroenterol 1997;92: 582–585. 7. Kuo B, Castell DO. Optimal dosing of omeprazole 40 mg daily: effects on gastric and esophageal pH and serum gastrin in healthy controls. Am J Gastroenterol 1996;91:1532–1538. 8. Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology 1998;115:1335–1339.

Reply. We thank Drs. Castell and Katzka for their interest in our work. One of the emerging questions in the medical management of patients with Barrett’s esophagus is the significance of complete intraesophageal acid suppression. Our experimental1 and clinical data2 indeed support the notion that effective intraesophageal acid suppression may be beneficial in the long-term management of Barrett’s esophagus. The exact degree of such suppression is not known and has not yet been tested. We agree with Drs. Castell and Katzka that our ‘‘normalization’’ of acid exposure may not have been stringent enough particularly in view of our ex vivo data suggesting that even small acid pulses may be

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detrimental to the Barrett’s epithelium. In response to their letter, we investigated whether patients who were more profoundly acid suppressed (i.e., had no evidence of nocturnal reflux) had an even more marked reduction in PCNA expression and induction of villin expression. The results were not significant because of the small sample size (23 of the 26 patients from group A vs. 3 patients; see Table 2). Peghini et al.3 first observed nocturnal intragastric acid breakthrough, defined as recovery of nocturnal acid secretion (intragastric pH , 4) lasting more than 1 hour within 12 hours of an evening dose of a PPI in both patients with gastroesophageal reflux disease and controls maintained on twice daily PPI therapy. In a follow-up study,4 these investigators also showed that such intragastric acid breakthrough is better controlled with a nighttime dose of a histamine H2-receptor antagonist than with a PPI. Together with our data, this observation is intriguing and will require further evaluation to prove its clinical relevance. Duodenogastroesophageal (bile) reflux with or without acid and its potential for esophageal mucosal damage, Barrett’s dysplasia, and/or adenocarcinoma may also play a role.5 Therefore, we concur with Drs. Castell and Katzka that a long-term multicenter, prospective trial using more effective acid control (PPIs with or without H2-receptor antagonists and confirmed by pH studies) will be the only way to find out if we can prevent dysplasia and adenocarcinoma in patients with Barrett’s esophagus. RODICA OUATU–LASCAR, M.D. Department of Medicine Wayne State University School of Medicine Detroit, Michigan REBECCA C. FITZGERALD, M.D. Digestive Diseases Research Centre St. Bartholomew’s and The Royal London School of Medicine and Dentistry London, England GEORGE TRIADAFILOPOULOS, M.D. Gastroenterology Division Stanford University School of Medicine Stanford, California 1. Fitzgerald RC, Omary MB, Triadafilopoulos G. Dynamic effects of acid on Barrett’s esophagus: an ex vivo proliferation and differentiation model. J Clin Invest 1996;98:2120–2128. 2. Ouatu-Lascar R, Fitzgerald RC, Triadafilopoulos G. Differentiation and proliferation in Barrett’s esophagus and the effects of acid suppression. Gastroenterology 1999;117:327–335. 3. Peghini PL, Katz PO, Bracy NA, et al. Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors. Am J Gastroenterol 1998;93:763–767. 4. Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology 1998;115:1335–1339. 5. Stein HJ, Kauer WKH, Feussner H, et al. Bile acids as components of the duodenogastric refluxate: detection, relationship to bilirubin, mechanism of injury, and clinical relevance. Hepatogastroenterology 1999;46:66–73.

Low-Dose Methotrexate in Primary Biliary Cirrhosis Dear Sir: An article by Hendrickse et al.1 and an accompanying editorial2 suggest that methotrexate given at a dose of 7.5 mg/wk is ineffective for primary biliary cirrhosis (PBC) and that methotrexate has no role in the care of patients with PBC outside of clinical trials. We have concerns about these conclusions for many reasons.

December 1999

• The dose of methotrexate used was substantially lower than has been established to be effective in other reports. • The toxicity of methotrexate described in the accompanying editorial was exaggerated. • The conclusion that a favorable biochemical response to methotrexate is an inadequate measure of efficacy is not substantiated by the available data. • Options available to patients with PBC who do not respond to ursodeoxycholic acid (UDCA) are limited. These patients may represent a subgroup who respond to combination therapy. The optimal dose of methotrexate for the treatment of autoimmune disorders including PBC has not been established. In patients with rheumatoid arthritis, the usual starting dose is 7.5 mg weekly, and is adjusted according to efficacy. Maintenance doses are typically in the range of 11.5–17 mg weekly.3,4 We and others have found that the minimal effective dose for PBC is 0.25 mg · kg body wt21 · wk21, or 12.5–20 mg/wk.5,6 In our experience, all patients with PBC who responded to methotrexate had worsening liver biochemical test results and symptoms when the dose was decreased to 10 mg/wk or lower. Furthermore, histological amelioration has usually been confined to patients whose liver biochemical tests reach normal or near normal levels, and only after prolonged treatment.5 Thus, it is unlikely that the fixed dose of 7.5 mg used by Hendrickse et al.1 was adequate to favorably influence endpoints such as liver histology and survival. The discussion of the toxicity in the accompanying editorial greatly overstates the risk of low-dose methotrexate. As an example, although we reported a 14% incidence of pneumonitis in a cohort of patients treated before 1994,7 we have not seen a case since while having treated many more patients. In another preliminary report,8 no lung toxicity was found in 265 patients (approximately half receiving methotrexate) who had been followed for up to 4 years in a trial of methotrexate plus UDCA compared with UDCA alone. When pneumonitis has occurred, it responded within less than 24 hours to the same prednisone regimen used to treat poison ivy. Other side effects are also uncommon. We have not observed abdominal pain in any patient. Mucositis (aphthous ulcers) is infrequent, ,5%, and usually remits spontaneously when methotrexate is continued with folic acid supplements. Bone marrow suppression is equally uncommon with low-dose methotrexate, ,1% in our experience, and even lower in patients with rheumatoid arthritis. The impression that methotrexate is associated with a greater incidence of bone marrow depression in PBC may be due to cytopenia associated with coexisting portal hypertension and hypersplenism caused by the underlying liver disease. At least 500,000 Americans with rheumatoid arthritis take similar amounts of methotrexate discussed above. Side effects are usually minimal and are far outweighed by the benefits of therapy. We are disappointed that unwarranted fear of methotrexate toxicity has delayed its use in PBC just as equally unwarranted fear of azathioprine and 6-mercaptopurine delayed their widespread use in Crohn’s disease for more than 30 years. In their editorial, Angulo and Dickson2 comment that ‘‘serum levels of alkaline phosphatase, g-glutamyltransferase, aminotransferases, and immunoglobulins have not been identified as independent predictors of disease progression in untreated PBC patients.’’ While the statement is correct, all of the models referred to looked only at predictors of death or liver transplantation. None evaluated the opposite, namely, improvement, because there was no effective treatment when these models were developed. Furthermore, these surrogate markers improved in 3 large controlled trials that led to the approval of ursodiol by the Food and Drug Administration.9–11

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Evidence from randomized controlled trials represents the most credible source of information for evaluating the efficacy of an intervention. Thus, the negative results from a controlled trial of methotrexate in PBC are regrettable, especially considering the limitations discussed above and the small number of patients. Despite these results, uncontrolled sources of data should not be overlooked, particularly in patients with PBC in whom the disease progresses despite treatment with UDCA. Such patients may represent a subgroup who could benefit from additional therapy. We described 10 patients with persistent increases in serum alkaline phosphatase levels despite UDCA who responded to the combination of UDCA, colchicine, and methotrexate.12 Although the study was uncontrolled and had insufficient follow-up to show a survival benefit, the data are sufficiently compelling to warrant consideration of such therapy in patients who are otherwise destined for liver transplantation. It will be many years before the results of controlled trials of combination therapy will be available, during which time many such patients will experience progression of their disease. It is unrealistic to expect that all such patients will have access to the handful of medical centers conducting controlled trials. Thus, we believe it is reasonable to consider combination therapy in patients with PBC whose disease is progressing despite UDCA. PETER A. L. BONIS, M.D. MARSHALL M. KAPLAN, M.D. Division of Gastroenterology Tufts University School of Medicine Boston, Massachusetts 1. Hendrickse MT, Rigney E, Giaffer MH, et al. Low-dose methotrexate is ineffective in primary biliary cirrhosis: long-term results of a placebo-controlled trial. Gastroenterology 1999;117:400–407. 2. Angulo P, Dickson ER. Methotrexate in the treatment of primary biliary cirrhosis: the hype and the hope (editorial). Gastroenterology 1999;117:492–494. 3. Weinblatt ME, Weissman BN, Holdsworth DE, et al. Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis: 84 month update. Arthritis Rheum 1992;35:129–137. 4. Kremer JM. Safety, efficacy, and mortality in a long-term cohort of patients with rheumatoid arthritis taking methotrexate: follow-up after a mean of 13.3 years. Arthritis Rheum 1997;40:984. 5. Kaplan MM, DeLellis RA, Wolfe HH. Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment. Ann Intern Med 1997;126:682–688. 6. Buscher HP, Zietzxchmann Y, Gerok W. Positive responses to methotrexate and ursodeoxycholic acid in patients with primary biliary cirrhosis responding insufficiently to ursodeoxycholic acid. J Hepatol 1993;1:9–14. 7. Sharma A, Provenzale D, McKusick A, et al. Interstitial pneumonitis after low-dose methotrexate therapy in primary biliary cirrhosis. Gastroenterology 1994;107:266–270. 8. Munoz S, Carithers L, Emerson SS, et al. Absence of pulmonary toxicity in primary biliary cirrhosis (PBC) treated with methotrexate and ursodiol (abstr). Hepatology 1998;28:392A. 9. Poupon RE, Poupon R, Balkau B. Ursodiol for the long-term treatment of primary biliary cirrhosis. N Engl J Med 1994;330: 1342–1347. 10. Heathcote EJ, Cauch-Dudek K, Walker V, et al. The Canadian multicenter double-blind randomized controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1994;19:1149– 1156. 11. Lindor KD, Dickson ER, Baldus WP, et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology 1994; 106:1284–1290. 12. Bonis PAL, Kaplan M. Methotrexate improves biochemical tests in patients with primary biliary cirrhosis who respond incompletely to ursodiol. Gastroenterology 1999;117:395–399.

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Reply. We disagree with several of the points made by Drs. Bonis and Kaplan. It is possible that the dose of methotrexate in our study1 was too low for clinical efficacy, but this remains speculative. The published literature (including references 5 and 6) cited by Bonis and Kaplan does not suggest that the minimal effective dose of methotrexate for PBC exceeds 10 mg/wk. Dr. Kaplan’s group has, to our knowledge, reported only 1 case2,3 in which liver enzyme levels worsened on reduction of the dose to less than 10 mg/wk. Furthermore, in an prospective comparison of 7.5 and 15 mg/wk methotrexate in PBC,4 symptomatic and biochemical responses did not differ significantly between the 2 groups. In published studies, using approximately 15 mg/wk methotrexate in PBC, the drug was stopped or its dose reduced in 21% (26/122) patients because of adverse effects.4–9 Thus we do not agree that fear of methotrexate toxicity is ‘‘unwarranted’’ or that the editorial by Drs. Angulo and Dickson10 ‘‘greatly overstated’’ the toxicity of methotrexate at this dose. It is intriguing that, having reported in 1994 a 14% incidence of interstitial pneumonitis associated with methotrexate in PBC,5 Dr. Kaplan’s group has ‘‘not seen a case since.’’ Do they have any explanation for this? Bonis and Kaplan contend that ‘‘the conclusion that a favorable biochemical response to methotrexate is an inadequate measure of efficacy is not substantiated by the available data.’’ We assume that by efficacy is meant prevention of liver-related death or transplantation and of deterioration in prognostic parameters such as serum bilirubin and Mayo score. Despite some anecdotal evidence from Dr. Kaplan’s group,3 the predictive value of the early liver enzyme response for long-term efficacy of methotrexate has not been systematically assessed. Indeed, this predictive value might be called into question by our results suggesting that, despite decreases in serum liver enzyme and immunoglobulin levels, methotrexate treatment was associated with a trend toward a worse long-term outcome.1 Further analysis of the 30 patients who received methotrexate (Gleeson et al., unpublished data) suggests no trends toward any difference (by AOCV to allow for baseline differences) in on-treatment serum aspartate and alanine aminotransferase, alkaline phosphatase, g-glutamyltransferase, or immunoglobulin M levels between those patients who died of liver disease or underwent transplantation (n 5 8) and those who did not (n 5 22). Similarly, as far as we are aware, the long-term predictive value of the early liver enzyme response has not been established for UDCA or for any other treatment for PBC. In the absence of such information, reports of favorable liver enzyme responses to a treatment strategy in PBC are hardly, in themselves, a basis for changing clinical practice. Finally, although medical treatment options in patients with PBC who do not respond to UDCA are indeed limited, a highly effective salvage treatment exists—liver transplantation. Thus, there is rarely a clinical imperative for medical interventions of unproved efficacy and potential toxicity. We believe, with Drs. Angulo and Dickson,10 that use of methotrexate in PBC that continues to progress despite UDCA treatment should presently be confined to clinical trials. DERMOT GLEESON JAMES C. E. UNDERWOOD MARK T. HENDRICKSE MUSTAPHA H. GIAFFER Gastroenterology and Liver Unit and Department of Pathology Royal Hallamshire Hospital Sheffield, England 1. Hendrickse MT, Rigney E, Giaffer MH, et al. Low-dose methotrexate is ineffective in primary biliary cirrhosis: long-term results of a placebo-controlled trial. Gastroenterology 1999;117:400–407.

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2. Kaplan MM, Knox TA. Treatment of primary biliary cirrhosis with low-dose weekly methotrexate. Gastroenterology 1991;101:1332– 1338. 3. Kaplan MM, DeLellis RA, Wolfe HJ. Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment. Ann Intern Med 1997;126:682–688. 4. Conjeevaram HS, Bergasa NV, Kleiner DE, et al. Methotrexate therapy of primary biliary cirrhosis: 2 yr study comparing two different doses (abstr). Hepatology 1995;22:124A. 5. Sharma A, Provenzale S, McKusick A, et al. Interstitial pneumonitis after low-dose methotrexate in primary biliary cirrhosis. Gastroenterology 1994;107:266–270. 6. Buscher HP, Zeitzschmann Y, Gerok W. Positive responses to methotrexate and ursodeoxycholic acid in patients with primary biliary cirrhosis responding insufficiently to ursodeoxycholic acid alone. J Hepatol 1993;18:9–14. 7. Bergasa NV, Jones EA, Kleiner DE, et al. Pilot study of low-dose oral methotrexate treatment for primary biliary cirrhosis. Am J Gastroenterol 1996;91:295–299. 8. Lindor KD, Dickson ER, Jorgensen RA, et al. The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis: the results of a pilot study. Hepatology 1995;22: 1158–1162. 9. Vandeputte L, Van Steenbergen W. Methotrexate therapy in primary biliary cirrhosis is of limited efficacy and is accompanied by serious side effects (abstr). Gastroenterology 1997;112: A1406. 10. Angulo P, Dickson ER. Methotrexate treatment of primary biliary cirrhosis: the hype and the hope (editorial). Gastroenterology 1999;117:492–494.

Reply. We appreciate the comments by Drs. Bonis and Kaplan. Unfortunately, the interpretation that methotexate is a safe drug in PBC has not been a consistent experience. We commented on several adverse events1–5 in our editorial. Caution must be exercised in extrapolating the apparent safety of methotrexate in rheumatoid arthritis to patients with chronic cholestatic liver disease. The hepatotoxic effects of methotrexate may be greater in patients with underlying liver disease than in rheumatoid patients with an otherwise normal liver: this is further supported by the study by Hendrickse et al.6 showing that low-dose methotrexate is not only of no benefit in PBC but associated with a more unfavorable outcome compared with placebo. Even if one assumes that methotrexate is a safe drug, we still do not have enough data to recommend its routine use in patients with PBC. The reported benefit achieved with methotrexate therapy in a few selected PBC patients7–9 has not been confirmed in larger trials,2,3,6,10–12 even with the dose of 15 mg/wk.2,3,10–12 Hence, caution in recommending methotrexate in the treatment of PBC is not because of ‘‘unwarranted fear,’’ but rather the lack of convincing evidence of long-term benefit. As pointed out in our editorial, it is uncertain if a greater dosage of methotrexate than that used by Hendrickse et al. (7.5 mg/wk)6 could have been of some benefit. Against this, however, are the results of the single study reported comparing different dosages of methotrexate in PBC.4 Similar results were obtained using 7.5 or 15 mg/wk.4 Also, it is difficult to uphold the dose of 0.25 mg · kg21 · wk21 as the most effective one based only on reports of a few isolated cases.7,8 UDCA is the only medication approved by the FDA in the treatment of PBC based on its safety and beneficial effects in improving not only liver chemistries, but clinically relevant endpoints such as death and need for liver transplantation.13–16 Further studies are required to show that the improvement of several liver chemistries reported during methotrexate therapy in some PBC patients corresponds with an improved prognosis.

December 1999

We agree that results of uncontrolled trials should not be overlooked and that PBC patients with an incomplete response to UDCA should be considered as candidates for treatment with combination therapy. We believe that results of case series reports or pilot, uncontrolled trials are helpful in the design of randomized, controlled trials, but we do not think that such limited reports are sufficient to base recommendation for routine administration of the drug. This is particularly true when negative results have been reported with the medication in several other trials. Fortunately, clinical trials evaluating now promising drugs in combination with UDCA in previously untreated PBC patients as well as in patients with a suboptimal response to UDCA alone are now under way, and their results will be available in the near future. Similarly, the results of an upcoming, large-scale, randomized, controlled trial of methotrexate in PBC17 will further clarify the role of methotrexate in patients with PBC. As the results of these studies become available, physicians will be in a better position to determine appropriate treatment for patients with PBC. PAUL ANGULO E. ROLLAND DICKSON Division of Gastroenterology and Hepatology Mayo Clinic and Foundation Rochester, Minnesota 1. Bergasa NV, Jones EA, Kleiner DE, et al. Pilot study of low-dose oral methotrexate treatment for primary biliary cirrhosis. Am J Gastroenterol 1996;91:295–299. 2. Lindor KD, Dickson ER, Jorgensen RA, et al. The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis: the results of a pilot study. Hepatology 1995;22: 1158–1162. 3. Valndeputte L, Van Streenbergen W. Methotrexate therapy in primary biliary cirrhosis is of limited efficacy and accompanied by serious side effects (abstr). Gastroenterology 1997;112:A1406. 4. Conjeevaram HS, Bergasa NV, Kleiner DE, et al. Methotrexate therapy of primary biliary cirrhosis: 2 yr study comparing two doses (abstr). Hepatology 1995;22:124A. 5. Sharma A, Provenzale D, McKusick A, et al. Interstitial pneumonitis after low-dose methotrexate therapy in primary biliary cirrhosis. Gastroenterology 1994;107:266–270. 6. Hendrickse MT, Rigney E, Giaffer MH, et al. Low-dose methotrexate is ineffective in primary biliary cirrhosis: long-term results of a placebo-controlled trial. Gastroenterology 1999;117:400–407. 7. Buscher HP, Zietzschmann Y, Gerok W. Positive response to methotrexate and ursodeoxycholic acid in patients with primary biliary cirrhosis responding insufficiently to ursodeoxycholic acid alone. J Hepatol 1993;18:9–14. 8. Kaplan MM, DeLellis RA, Wolfe HH. Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment. Ann Intern Med 1997;126:682–688. 9. Bonis PAL, Kaplan MM. Methotrexate improves biochemical tests in patients with primary biliary cirrhosis who responded incompletely to ursodiol. Gastroenterology 1999;117:395–399. 10. Gonzalez-Koch A, Brahm J, Antezana C, et al. The combination of ursodeoxycholic acid and methotrexate for primary biliary cirrhosis is not better than ursodeoxycholic acid alone. J Hepatol 1997;27:147–149. 11. Bach N, Thung SN, Shaffner F. The histologic effects of low-dose methotrexate therapy for primary biliary cirrhosis. Arch Pathol Lab Med 1998;122:342–345. 12. Bach N, Bodian C, Thung S, et al. Methotrexate for primary biliary cirrhosis: five year follow-up (abstr). Hepatology 1998;28:545A. 13. Poupon RE, Poupon R, Balkau B, et al. Ursodiol for the treatment of primary biliary cirrhosis. N Engl J Med 1994;330:1342–1347. 14. Lindor KD, Therneau TM, Jorgensen RA, et al. Effects of ursode-

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oxycholic acid on survival of patients with primary biliary cirrhosis. Gastroenterology 1996;110:1515–1518. 15. Emmond M, Carithers RL Jr, Luketic VA, et al. Does ursodeoxycholic acid improve survival in patients with primary biliary cirrhosis? Comparison of outcome in the U.S. multicenter trial to expected survival using the Mayo prognostic model (abstr). Hepatology 1996;24:168A. 16. Poupon RE, Lindor KD, Kauch-Dudek K, et al. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997;113:884–890. 17. Munoz S, Carithers RL Jr, Emerson SS, et al. Absence of pulmonary toxicity in primary biliary cirrhosis (PBC) treated with methotrexate and ursodiol (abstr). Hepatology 1998;28:392A.

Balsalazide and Azathioprine or 6-Mercaptopurine Response to a Letter Appearing in June 1999 Reply. In the June 1999 issue of GASTROENTEROLOGY, Lowry et al.1 in a Letter to the Editor provided a word of caution for the concomitant use of 5-aminosalicylic acid (5-ASA) agents and azathioprine/6-mercaptopurine (6-MP). They refer to in vitro data showing that 5-ASA and its prodrugs (olsalazine, sulfasalazine, balsalazide) inhibit thiopurine methyltransferase (TPMT), an enzyme that metabolizes both azathioprine and 6-MP. The inhibition might lead to increased levels of 6-thioguanine nucleotides that in turn could result in hazardous myelosuppression, particularly in vulnerable patients (e.g., leukemic patients or patients with a genetically low TPMT activity). The reported in vitro experiments resulted in IC50 values (concentrations where TPMT activity was halved) of 31, 104, 197, and 1380 µmol/L for olsalazine, sulfasalazine, balsalazide, and 5-ASA, respectively. The authors extrapolated these results into a call for caution when balsalazide is to be used together with immunosuppressive therapy with azathioprine/6-MP. Figure 1 shows plasma concentrations measured after oral administrations of single doses of balsalazide (2.25 g), 5-ASA (Asacol, 0.8 g), sulfasalazine (2.0 g), and olsalazine (1.0 g) in healthy subjects. It can be seen that the peak plasma concentration of intact balsalazide is extremely low (median, 0.06 µmol/L). The concentration declines rather fast, and therefore no accumulation of balsalazide should occur during repeated administration. Thus, peak plasma concentrations of balsalazide achieved with therapeutic doses of balsalazide are far below

Figure 1. Plasma concentrations of 5-ASA drugs after single oral therapeutic doses. Median concentrations are shown for 2.25 g balsalazide, 0.8 g 5-ASA, and 2.0 g sulfasalazine (data on file, AstraZeneca R&D Lund, Sweden). Mean concentrations after 1.0 g olsalazine have been extracted from Ryde and Ahnfelt.2