- Email: [email protected]
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creased esophageal sensory perception.9 In addition, basing a separation on the finding of ‘‘vigorous’’ achalasia in only 10 patients seems premature considering controversy over the clinical relevance of this manometric finding.10 However, the dramatic success shown by Pasricha et al. with this latter category may provide some reasonable justification for its use. BoTx injection may well have a role, although limited, in the treatment of patients with achalasia. However, at present we are distracted by the enthusiasts who are reaching for their endoscope and injection needle as primary treatment for these patients and ignoring the marvelous long-term success rate of pneumatic dilatation and myotomy. We hope to temper their zeal by reminding them to review the early enthusiasm, and eventual failure, of other techniques, such as the Guerin balloon and the Angelchik prosthesis! BoTx injection as long-term therapy for achalasia? To be or not to be? That is the question indeed. DONALD O. CASTELL DAVID A. KATZKA
Department of Medicine Graduate Hospital University of Pennsylvania Philadelphia, Pennsylvania
References 1. Pasricha PJ, Ravich WJ, Kalloo AN. Effects of intrasphincteric botulinum toxin on the lower esophageal sphincter in piglets. Gastroenterology 1993;105:1045–1049.
2. Pasricha PJ, Ravich WJ, Hendrix TR, Sostre S, Jones B, Kalloo AN. Treatment of achalasia with intrasphincteric injection of botulinum toxin—a pilot trial. Ann Intern Med 1994;121:590–591. 3. Pasricha PJ, Ravich WJ, Hendrix TR, Sostre S, Jones B, Kalloo AN. Intrasphincteric botulinum toxin for the treatment of achalasia. N Engl J Med 1995;332:774–778. 4. Pasricha PJ, Rai R, Ravich WJ, Hendrix TR, Kalloo AN. Botulinum toxin for achalasia: long-term outcome and predictors of response. Gastroenterology 1996;110:1410–1415. 5. Janckovic J, Brin MF. Therapeutic uses of botulinum toxin. N Engl J Med 1991;324:1186–1194. 6. Bansal R, Scheiman JM, Barnett JL, Nostrant TT. A randomized trial of Witzel pneumatic dilatation vs. intrasphincteric injection of botulinum toxin for achalasia (abstr). Gastroenterology 1995; 108:A52. 7. Schroeder P, Slaughter R, Torbey C, Morgan D, Koehler R, Richter J. Treatment of achalasia: botulinum toxin vs pneumatic dilatation. Am J Gastroenterol 1995;90:72. 8. Katz P. Achalasia: two effective treatment options—let the patient decide. Am J Gastroenterol 1994;89:969–970. 9. Lasch H, Castell DO. Evidence for diminished visceral pain with aging: studies using graded esophageal balloon distension (BD) (abstr). Gastroenterology 1994;106:1035. 10. Goldenberg SP, Burrell M, Gette GG, Vos C, Traube M. Classic and vigorous achalasia: a comparison of manometric, radiographic, and clinical findings. Gastroenterology 1991;101:743– 748.
Address requests for reprints to: Donald O. Castell, M.D., Department of Medicine, Graduate Hospital, 1800 Lombard Street, Philadelphia, Pennsylvania 19146. Fax: (215) 893-2472. 䉷 1996 by the American Gastroenterological Association 0016-5085/96/$3.00
Methotrexate and Ulcerative Colitis: Wrong Drug? Wrong Dose? Or Wrong Disease? See article on page 1416.
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mmunosuppressive therapy for noxious forms of inflammatory bowel disease has received increasing acceptance over the past two decades.1 – 6 In 1996, however, it remains ill-defined what place methotrexate should play in this treatment strategy. Originally synthesized by Seeger et al. in the 1940s,7 methotrexate is a folic acid analogue that inhibits dihydrofolate reductase and other folate-dependent enzymes.8,9 Such inhibition results in decreased purine synthesis and reduction of transmethylation reactions at the cellular level and was the basis for methotrexate’s initial application in 1953 for / 5e0d$$0054
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the treatment of childhood leukemia.10,11 More recently, low-dose methotrexate has been noted to cause qualitative and quantitative changes in both B- and T-cell function and consequent cytokine production (suppression of interleukin-1 production and functional activity and interleukin-6 activity).12 – 16 These effects and the direct effects on the inflammatory response (decreased chemotaxis for polymorphonuclear leukocytes, decreased synthesis of leukotriene B4 , and depressed generation of superoxide)17 – 22 have led to the use of low-dose methotrexate for a variety of chronic inflammatory conditions, diseases associated with increased cellular turnover, and diseases believed to be immunologically mediated. As such, methotrexate has become standard therapy for noxWBS-Gastro
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ious forms of psoriasis23 and rheumatoid arthritis24 and has been used with varying degrees of enthusiasm and acceptance for other collagen-vascular or vasculitic-type diseases,25,26 refractory asthma,27 and even certain chronic liver conditions.28 – 30 In 1989, our group reported results of a preliminary clinical trial suggesting that methotrexate may also have a role to play in refractory inflammatory bowel diseases.31 This study treated 14 patients with Crohn’s disease and 9 patients with chronic ulcerative colitis with 25 mg of parenteral methotrexate weekly for a 12-week study period. Approximately 75% of the patients in both groups had significant improvement as defined clinically and reduction in dose or elimination of corticosteroids. A subset of patients with Crohn’s disease had dramatic healing in colonic lesions as defined endoscopically and histologically. In contrast, no patient with ulcerative colitis showed endoscopic or histological remission. Furthermore, when followed up for approximately 18 months, only 40% of patients with chronic ulcerative colitis who went into clinical remission with parenteral therapy sustained that remission with 7.5–15 mg of oral methotrexate weekly.32 Since that initial report, there has been a paucity of additional trials using methotrexate for refractory or steroid-dependent inflammatory bowel disease. An openlabel study by Baron et al. used a gradually increasing dose, ultimately using 15 mg weekly for 15 weeks (2.5 mg, week 1; 5 mg, week 2; and 10 mg, week 3).33 Prednisone dosage for 10 patients with Crohn’s disease decreased from a mean of 37 { 9.6 to 8.3 { 2 mg/day (P õ 0.02). Six patients sustained a response (2 complete, 4 partial). In the 8 patients with chronic ulcerative colitis, the daily prednisone dose decreased from 26.3 { 3.2 to 12.7 { 2.0 mg/day (P õ 0.001), and 3 patients had a partial clinical response. Drug-related side effects were considered mild. Chamiot-Prieur et al. treated 39 patients with refractory Crohn’s disease for 12 weeks with 25 mg of parenteral methotrexate weekly followed by a tapering oral dose.34 Clinical remission at 1, 3, and 6 months was 53%, 72%, and 72%, respectively (life table analysis). Mean prednisone dose was 20.4 mg at the study initiation and 7.5 mg (P õ 0.05) at 6 months. Minor side effects were common (gastrointestinal symptoms, vertigo, and headache; 56%) but necessitated drug discontinuation in only 4 patients. Seventy-five percent of the patients had discontinued methotrexate within 18 months because of recurrent symptoms, noncompliance (13%), toxicity (10%), or sustained remission (5%). Before the study by Oren et al.35 reported in this issue of GASTROENTEROLOGY, there have been only two controlled trials using methotrexate for refractory in/ 5e0d$$0054
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flammatory bowel disease, both for Crohn’s disease. In one, Arora et al. administered methotrexate, 5 mg orally three times weekly, or placebo for 52 weeks to steroiddependent patients with Crohn’s disease followed by an attempt at steroid tapering.36 Fifty-four percent of patients in the methotrexate group remained in remission opposed to 20% in the placebo group (P Å 0.06). Feagan et al., in turn, treated 141 steroid-dependent patients with either placebo (n Å 47) or 16 weeks of 25 mg of weekly methotrexate (n Å 94).37 Approximately twice as many methotrexate-treated patients entered remission (39.4% vs. 19.1%; P Å 0.03) despite cessation of steroids. The patients receiving the active drug had a significantly lower Crohn’s Disease Activity Index (162 { 12 vs. 204 { 17; P Å 0.002) and received less prednisone overall (P Å 0.026). Seventeen percent of patients receiving the active drug were withdrawn from treatment for adverse events (6 with nausea, 7 with asymptomatic liver function test elevations) vs. 2% in the placebo group. This multicenter group is currently enrolling patients in a long-term placebo-controlled trial to determine the efficacy of 15 mg of oral methotrexate weekly on remission maintenance. From the standpoint of science, the report by Oren et al.35 is a well-done study. It is the first controlled trial using methotrexate for chronic ulcerative colitis. Randomizing 67 patients with active disease who had required either immunosuppressives or ¢5 mg of prednisone for 4 of the preceding 12 months to groups receiving either placebo (n Å 37) or 12.5 mg of oral methotrexate weekly (n Å 30), the authors showed a virtually identical response for the two groups after 9 months of treatment. This included proportion of patients entering first remission (approximately 50%), time to reach the first remission (3–4 months), and subsequent relapse (methotrexate, 64%; placebo, 44%; P Å NS). The mean Mayo Clinic score (composite of degree of bleeding, stool frequency, sigmoidoscopic findings, and physicians’ global assessment [remission defined °3, relapse ¢3 points]) were comparable, as were monthly steroid dose and abnormal laboratory study findings. Approximately two-thirds of both groups were receiving steroids and/or mesalamine products at study initiation, whereas the placebo-treated group was less likely to have received previous immunosuppressive agents (17% vs. 34%). There were 9 dropouts in the placebo-treated patients vs. 2 (P Å 0.052) in patients receiving methotrexate. The authors concluded that a weekly dose of 12.5 mg of methotrexate was ineffective in treating chronic active ulcerative colitis. This is a well-presented paper, and the statistical power of the study to detect a 30% difference between the two groups was 98.6%. Unfortunately, it leaves many WBS-Gastro
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questions unanswered. The easy one is: where was the toxicity in patients receiving the active drug? In my practice and in the previously mentioned studies,31 – 34,36,37 initiation of oral methotrexate in the doses used engenders nausea and a 24-hour exacerbation of diarrhea in up to a quarter of patients. These side effects are often minimized by initiation with parenteral therapy, whereas transaminase level elevations and the number of occasional cases of alopecia, stomatitis, and skin rash are comparable. At any rate, data in the rheumatologic literature clearly show that folic acid supplementation minimizes some of methotrexate’s side effects without changing drug efficacy.38 As such, and in contrast to the current study, all patients treated with methotrexate in our unit now receive concomitant folic acid supplementation.39 Was the dose chosen the correct one? Although this clearly requires further study both in chronic ulcerative colitis and Crohn’s disease, one wonders whether the paucity of side effects in the current study has any relationship to lack of response. In the 16-week study by Feagan et al., side effects in the 94 patients receiving 25 mg of the active drug included abnormalities in liver function test results (5%), nausea (4%), skin rash (1%), and pneumonitis (1%).37 I know of no study that has examined whether patients who developed side effects were more likely to have a clinical response. At least some of methotrexate’s side effects are idiosyncratic (e.g., hypersensitivity and pneumonitis), are related to concomitant drugs (alcohol or trimethoprimsulfamethoxazole), or are a consequence of cumulative dose (hepatic fibrosis).40,41 My experience in chronic ulcerative colitis suggests that doses õ20–25 mg weekly are unlikely to induce remission, and it is unusual in my practice to maintain a remission in chronic ulcerative colitis with õ15 mg weekly. Higher doses have also been shown to be effective in patients with resistant rheumatoid arthritis.42 Was the route of administration appropriate? Data show that methotrexate blood levels and bioavailability are reasonably comparable in most patients whether the drug is given orally or parenterally.43 – 46 The problem with using plasma levels, however, is that they bear no relation to clinical response when using low-dose therapy. This has been shown repeatedly in the rheumatologic literature and was also suggested by our original study.31 Parenteral methotrexate seems to be more effective in our experience and minimizes many of the gastrointestinal side effects noted with oral therapy. In my practice, approximately one-third of patients with Crohn’s disease treated with methotrexate are maintained on parenteral therapy (mean dose, 15 mg) either because of intolerance / 5e0d$$0054
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or relapse on initiation of oral therapy.32 This also deserves additional study. What is the long-term toxicity? Long-term toxicity should be zero for an ineffective drug. In other words, the drug should not be used. Assuming that there remain unanswered questions in both Crohn’s disease and chronic ulcerative colitis and that there is room for additional study, what can be said about prolonged methotrexate therapy? There are numerous reports in the dermatologic and rheumatologic literature showing that liver toxicity (fibrosis, cirrhosis) is a potential problem. Whereas the latter is uncommon in rheumatoid arthritis (approximately 1%),47 an incidence approximating 7% has been defined by meta-analysis when the drug is administered for psoriasis.48 Baseline abnormal liver function test results, concomitant alcohol use, a history of obesity or diabetes, daily administration of the drug, and a cumulative dose in excess of 1500 mg are all risk factors.41 Our unit currently interdicts alcohol absolutely and recommends liver biopsy at 1500, 3000, and 5000 mg. To date, no significant hepatopathology has been noted.49 Two other adverse events deserve mention with long-term therapy: hypersensitivity pneumonitis and bone marrow suppression. Whereas the latter can occur in up to a quarter of methotrexate-treated patients, most cytopenias are mild, reversible, and treated either by maintaining or reducing the dose.10,50,51 Patients who become folic acid depleted, those with renal insufficiency, or those taking simultaneous trimethoprim/sulfamethoxazole may occasionally develop profound suppression requiring leucovorin rescue and temporary drug discontinuation.42 Hypersensitivity pneumonitis, in turn, may be subtle, presenting with mild shortness of breath and a nonproductive cough or as fulminant pulmonary failure.53 Recognition is imperative and may require chest radiography, arterial blood gas measurements, pulmonary function studies to include carbon monoxide diffusing capacity, and even bronchoscopy with alveolar lavage. Occurring at any time during the course of therapy, treatment consists of methotrexate withdrawal, initiation of high-dose corticosteroid therapy, and occasionally ventilatory support.46 The randomized study by Oren et al.35 offers new insights into methotrexate use for inflammatory bowel disease. It is clear from the study that the drug has little to offer for chronic ulcerative colitis (not even toxicity) in the dose and route of administration selected. I await with interest the authors’ parallel study looking at a similar dosing regimen for refractory Crohn’s disease. Given previously published controlled studies showing clinical response to methotrexate for Crohn’s disease,31,32 lack of efficacy in this soon-to-be-completed study may WBS-Gastro
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imply an inadequate dose or route of administration. Efficacy, in turn, would at a minimum define discordant responses of the two disease processes to methotrexate. RICHARD A. KOZAREK
Section of Gastroenterology Virginia Mason Medical Center Seattle, Washington
References 1. Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pastenack BS. Treatment of Crohn’s disease with 6-mercaptopurine. A longterm, randomized, double-blind study. N Engl J Med 1980;302: 981–987. 2. Hawthorne AB, Logan RFA, Hawkey CJ, Foster PN, Axon AT, Swarbrick ET, Scott BB, Lennard-Jones JE. Randomized controlled trial of azathioprine withdrawal in ulcerative colitis. Br Med J 1992; 305:20–22. 3. Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S. Cyclosporin in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330: 1841–1845. 4. Kozarek RA. Review article: immunosuppressive therapy for inflammatory bowel disease. Aliment Pharmacol Ther 1993;7: 117–123. 5. Kornbluth A, George J, Sachar DB. Immunosuppressive drugs in Crohn’s disease. Gastroenterologist 1994;2:239–246. 6. Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: azathioprine; 6-mercaptopurine, cyclosporine, and methotrexate Am J Gastroenterol 1996;91:423– 433. 7. Seeger DR, Cosulich DB, Smith JM, Hultquist ME. Analogs of pteroylglutamic acid. 4-Amino derivatives. J Am Chem Soc 1949; 71:1753–1758. 8. White JC, Loftfield S, Goldman ID. The mechanism of action of methotrexate. III. Requirement of free intracellular methotrexate for maximal suppression of [14C]formate incorporation into nucleic acids and protein. Mol Pharmacol 1975;11:287–297. 9. Christophidis N. Methotrexate. Clin Rheum Dis 1984;10:401– 415. 10. Bleyer WA. The clinical pharmacology of methotrexate. New applications of an old drug. Cancer 1978;41:36–57. 11. Jolivet J, Cowan KH, Curt GA, Clendeninn NJ, Chabner BA. The pharmacology and clinical use of methotrexate. N Engl J Med 1983;309:1094–1104. 12. Segal R, Yaron M, Tartakovsky B. Methotrexate: mechanism of action in rheumatoid arthritis. Semin Arthritis Rheum 1990;20: 190–199. 13. Rosenthal GJ, Weigand GW, Germolec DR, Blank JA, Luster MI. Suppression of B cell function by methotrexate and trimetrexate. Evidence for inhibition of purine biosynthesis as a major mechanism of action. J Immunol 1988;141:410–416. 14. Brody M, Bohm I, Bauer R. Mechanism of action of methotrexate: experimental evidence that methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells. Eur J Clin Chem Clin Biochem 1993;31:667–674. 15. Weinstein GD, Jeffes E, McCullough JL. Cytotoxic and immunologic effects of methotrexate in psoriasis. J Invest Dermatol 1990;95:49S–52S. 16. Calabrese LH, Taylor JV, Wilke WS, Segal AM, Valenzuela R, Clough JD. Response of immunoregulatory lymphocyte subsets to methotrexate in rheumatoid arthritis. Cleve Clin J Med 1990; 57:232–241. 17. Kremer JM. The mechanism of action of methotrexate in rheumatoid arthritis: the search continues (editorial). J Rheumatol 1994; 21:1–5.
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18. Cronstein BA, Eberle MA, Gruber HA, Levin RI. Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. Proc Natl Acad Sci USA 1991;88:2441– 2445. 19. Nesher G, Moore TL. Effect of methotrexate on chemotaxis and superoxide production of normal monocytes. Arthritis Rheum 1989;32:S60. 20. Leroux JL, Damon M, Chavis C, Crastes de Paulet A, Blotman F. Effects of a single dose of methotrexate on 5- and 12-lipoxygenase products in patients with rheumatoid arthritis. J Rheumatol 1992;19:863–866. 21. Cronstein BN. Molecular mechanism of methotrexate action in inflammation. Inflammation 1992;16:411–423. 22. Sperling RI, Benincaso AI, Anderson RJ, Coblyn JS, Austen KF, Weinblatt ME. Acute and chronic suppression of leukotriene B4 synthesis ex vivo in neutrophils from patients with rheumatoid arthritis beginning treatment with methotrexate. Arthritis Rheum 1992;35:376–384. 23. Hanno R, Gruber GG, Owen LG, Callen JP. Methotrexate in psoriasis. A brief review of indications, usage, and complications of methotrexate therapy. J Am Acad Dermatol 1980;2:171–174. 24. Kremer JM, Phelps CT. Long term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Update after a mean of 90 months. Arthritis Rheum 1991;35:138–145. 25. Owen ET, Cohen ML. Methotrexate in Reiter’s disease. Ann Rheum Dis 1979;38:48–50. 26. Hoffman GS, Leavitt RY, Kerr GS, Fauci AS. The treatment of Wegener’s granulomatosis with glucocorticoids and methotrexate. Arthritis Rheum 1992;35:1322–1329. 27. Mullarkey MF, Blumenstein BA, Andrade WP, Bailey GA, Olason I, Wetzel CE. Methotrexate in the treatment of corticosteroiddependent asthma. A double-blind crossover study. N Engl J Med 1988;318:603–607. 28. Kaplan MM, Knox TA. Treatment of primary biliary cirrhosis with low-dose weekly methotrexate. Gastroenterology 1991;101: 1332–1336. 29. 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. 30. Knox TA, Kaplan MM. A double-blind, controlled trial of oral pulse methotrexate therapy in the treatment of primary sclerosing cholangitis. Gastroenterology 1994;106:494–499. 31. Kozarek RA, Patterson DJ, Gelfand MD, Botoman VA, Ball TJ, Wilske KR. Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989;110:353–356. 32. Kozarek RA, Patterson DJ, Gelfand MD, Ball T Jr, Botoman VA. Long-term use of methotrexate in inflammatory bowel disease: severe disease 3, drug therapy 2, seventh inning stretch (abstr). Gastroenterology 1992;702:A648. 33. Baron TA, Truss CD, Elson CO. Low-dose oral methotrexate in refractory inflammatory bowel disease. Dig Dis Sci 1993;38: 1851–1856. 34. Chamiot-Prieur C, Le´mann M, Mesnard B, Halphen M, Messing B, Modigliani R, Rambaud JC, Gendre JP, Gue´don C, Colombel JF. Treatment of refractory Crohn’s disease with methotrexate (abstr). Gastroenterology 1993;104:A680. 35. Oren R, Arber N, Odes S, Moshkowitz M, Keter D, Pomeranz I, Ron Y, Reisfeld I, Broide E, Lavy A, Fich A, Eliakim R, Patz J, Bardan E, Villa Y, Gilat T. Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial. Gastroenterology 1996;110:1416–1421. 36. Arora S, Katkov WN, Cooley J, Kemp A, Shapiro RA, Kelsey PB, Podolsky DK. A double-blind, randomized, placebo-controlled trial of methotrexate in Crohn’s disease (abstr). Gastroenterology 1992;102:A591. 37. Feagan BG, Rochon J, Fedorak RN, Irvine EJ, Wild G, Sutherland,
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40. 41.
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47.
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L, Steinhart AH, Greenberg GR, Gillies R, Hopkins M. Methotrexate for the treatment of Crohn’s disease. N Engl J Med 1995; 332:292–297. Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, Koopman WJ, Krumdieck CL, Alarcom GS. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med 1994; 121:833–841. Kozarek RA. Methotrexate for refractory Crohn’s disease: preliminary answers to definitive questions (editorial). Mayo Clin Proc 1996;71:104–105. Goodman TA, Polisson RP. Methotrexate: adverse reactions and major toxicities. Rheum Dis Clin North Am 1994;20:513–528. Egan LJ, Sandborn WJ. Methotrexate for inflammatory bowel disease: pharmacology and preliminary results. Mayo Clin Proc 1996;71:69–80. Furst DE, Koehnke R, Burmeister LF, Kohler J, Cargill I. Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. J Rheumatol 1989;16:313–320. Teresi ME, Crom WR, Choi KE, Mirro J, Evans WE. Methotrexate bioavailability after oral and intramuscular administration in children. J Pediatr 1987;110:788–792. Zimmerman J. Methotrexate transport in the human intestine: evidence for heterogeneity. Biochem Pharmacol 1992;43:2377– 2383. Lebbe C, Beyeler C, Gerber NJ, Reichen J. Intraindividual variability of the bioavailability of low dose methotrexate after oral administration in rheumatoid arthritis. Ann Rheum Dis 1994;53:475– 477. Moshkowitz M, Oren R, Tishler M, et al. The absorption of lowdose methotrexate in patients with inflammatory bowel disease. Dig Dis Sci (in press). Kremer JM, Alarcon GS, Lightfoot RW Jr, Wilkens RF, Furst DE,
48.
49.
50.
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52.
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Williams HJ, Dent PB, Weinblatt ME. Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. Arthritis Rheum 1994;37:316–328. Newman M, Auerbach R, Feiner H, Holzman RS, Shupack J, Migdal P, Culubret M, Camuto P, Tobias H. The role of liver biopsies in psoriatic patients receiving long-term methotrexate treatment: improvement in liver abnormalities after cessation of treatment. Arch Dermatol 1989;125:1218–1224. Kozarek RA, Bredfeldt JE, Rosoff LE, Patterson DJ, Fenster LF. Does chronic methotrexate cause liver toxicity when used for refractory inflammatory bowel disease (abstr)? Gastroenterology 1991;100:A221. Alcaron GS, Tracy IC, Blackburn WD Jr. Methotrexate in rheumatoid arthritis: toxic effects as the major factor in limiting longterm treatment. Arthritis Rheum 1989;32:671–676. Schnabel A, Gooss WL. Low-dose methotrexate in rheumatic diseases—efficacy, side effects and risk factors for side effects. Semin Arthritis Rheum 1994;23:310–327. Tishler M, Caspi D, Fishel B, Yaron M. The effects of leucovorin (folinic acid) on methotrexate therapy in rheumatoid arthritis patients. Arthritis Rheum 1988;31:906–908. Hargreaves MR, Mowat AG, Benson MK. Acute pneumonitis associated with low dose methotrexate treatment for rheumatoid arthritis: report of five cases and review of published reports. Thorax 1992;47:628–633.
Address requests for reprints to: Richard A. Kozarek, M.D., Section of Gastroenterology, Virginia Mason Medical Center, 1100 Ninth Avenue, P.O. Box 900 (C3-GAS), Seattle, Washington 98111. Fax: (206) 223-6379. 䉷 1996 by the American Gastroenterological Association 0016-5085/96/$3.00
The Role of Mast Cells in Gastrointestinal Inflammation See article on page 1482.
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linically, allergen-induced reactions are characterized by a biphasic response.1 Within minutes of exposure to an allergen, there is an immediate reaction, initiated by cross-linkage of specific immunoglobulin (Ig) E bound to high-affinity receptors (FceRI) on the surface of mast cells and basophils. The early reaction usually fades within 90 minutes but may be followed by a recurrence of symptoms several hours later. This socalled late-phase reaction is associated with a sustained inflammatory response, involving tissue infiltration by granulocytes and mononuclear cells. Allergic inflammation has been shown to be a component of allergic reactions in the skin, respiratory tract, and other tissues. Furthermore, it is generally accepted that recruited leukocytes present in the target tissue are key players in the pathogenesis of chronic allergic diseases. However, the / 5e0d$$0054
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participation of late-phase reactions in allergic gastrointestinal phenomena is unknown. In this issue, Wershil et al.2 show for the first time that pathological hallmarks of late-phase responses also occur during the course of an IgE-dependent reaction in the mouse stomach. Another important accomplishment of this study is the demonstration that allergic gastric inflammation is mast cell–dependent. The mast cell dependency was confirmed by examining the gastric reaction in mast cell–deficient W/Wv mice and W/Wv mice that had undergone selective reconstitution of gastric mast cell populations by the injection of bone marrowderived mast cells into the stomach wall. Whereas mast cell–deficient mice did not show IgE-dependent gastric inflammation, the gastric-reconstituted W/Wv mice developed a neutrophilic response that was similar to that of normal congenic mice. This finding was not entirely unexpected because previous studies have shown that mast cell degranulation can promote leukocyte infiltraWBS-Gastro
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creased esophageal sensory perception.9 In addition, basing a separation on the finding of ‘‘vigorous’’ achalasia in only 10 patients seems premature considering controversy over the clinical relevance of this manometric finding.10 However, the dramatic success shown by Pasricha et al. with this latter category may provide some reasonable justification for its use. BoTx injection may well have a role, although limited, in the treatment of patients with achalasia. However, at present we are distracted by the enthusiasts who are reaching for their endoscope and injection needle as primary treatment for these patients and ignoring the marvelous long-term success rate of pneumatic dilatation and myotomy. We hope to temper their zeal by reminding them to review the early enthusiasm, and eventual failure, of other techniques, such as the Guerin balloon and the Angelchik prosthesis! BoTx injection as long-term therapy for achalasia? To be or not to be? That is the question indeed. DONALD O. CASTELL DAVID A. KATZKA
Department of Medicine Graduate Hospital University of Pennsylvania Philadelphia, Pennsylvania
References 1. Pasricha PJ, Ravich WJ, Kalloo AN. Effects of intrasphincteric botulinum toxin on the lower esophageal sphincter in piglets. Gastroenterology 1993;105:1045–1049.
2. Pasricha PJ, Ravich WJ, Hendrix TR, Sostre S, Jones B, Kalloo AN. Treatment of achalasia with intrasphincteric injection of botulinum toxin—a pilot trial. Ann Intern Med 1994;121:590–591. 3. Pasricha PJ, Ravich WJ, Hendrix TR, Sostre S, Jones B, Kalloo AN. Intrasphincteric botulinum toxin for the treatment of achalasia. N Engl J Med 1995;332:774–778. 4. Pasricha PJ, Rai R, Ravich WJ, Hendrix TR, Kalloo AN. Botulinum toxin for achalasia: long-term outcome and predictors of response. Gastroenterology 1996;110:1410–1415. 5. Janckovic J, Brin MF. Therapeutic uses of botulinum toxin. N Engl J Med 1991;324:1186–1194. 6. Bansal R, Scheiman JM, Barnett JL, Nostrant TT. A randomized trial of Witzel pneumatic dilatation vs. intrasphincteric injection of botulinum toxin for achalasia (abstr). Gastroenterology 1995; 108:A52. 7. Schroeder P, Slaughter R, Torbey C, Morgan D, Koehler R, Richter J. Treatment of achalasia: botulinum toxin vs pneumatic dilatation. Am J Gastroenterol 1995;90:72. 8. Katz P. Achalasia: two effective treatment options—let the patient decide. Am J Gastroenterol 1994;89:969–970. 9. Lasch H, Castell DO. Evidence for diminished visceral pain with aging: studies using graded esophageal balloon distension (BD) (abstr). Gastroenterology 1994;106:1035. 10. Goldenberg SP, Burrell M, Gette GG, Vos C, Traube M. Classic and vigorous achalasia: a comparison of manometric, radiographic, and clinical findings. Gastroenterology 1991;101:743– 748.
Address requests for reprints to: Donald O. Castell, M.D., Department of Medicine, Graduate Hospital, 1800 Lombard Street, Philadelphia, Pennsylvania 19146. Fax: (215) 893-2472. 䉷 1996 by the American Gastroenterological Association 0016-5085/96/$3.00
Methotrexate and Ulcerative Colitis: Wrong Drug? Wrong Dose? Or Wrong Disease? See article on page 1416.
I
mmunosuppressive therapy for noxious forms of inflammatory bowel disease has received increasing acceptance over the past two decades.1 – 6 In 1996, however, it remains ill-defined what place methotrexate should play in this treatment strategy. Originally synthesized by Seeger et al. in the 1940s,7 methotrexate is a folic acid analogue that inhibits dihydrofolate reductase and other folate-dependent enzymes.8,9 Such inhibition results in decreased purine synthesis and reduction of transmethylation reactions at the cellular level and was the basis for methotrexate’s initial application in 1953 for / 5e0d$$0054
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the treatment of childhood leukemia.10,11 More recently, low-dose methotrexate has been noted to cause qualitative and quantitative changes in both B- and T-cell function and consequent cytokine production (suppression of interleukin-1 production and functional activity and interleukin-6 activity).12 – 16 These effects and the direct effects on the inflammatory response (decreased chemotaxis for polymorphonuclear leukocytes, decreased synthesis of leukotriene B4 , and depressed generation of superoxide)17 – 22 have led to the use of low-dose methotrexate for a variety of chronic inflammatory conditions, diseases associated with increased cellular turnover, and diseases believed to be immunologically mediated. As such, methotrexate has become standard therapy for noxWBS-Gastro
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ious forms of psoriasis23 and rheumatoid arthritis24 and has been used with varying degrees of enthusiasm and acceptance for other collagen-vascular or vasculitic-type diseases,25,26 refractory asthma,27 and even certain chronic liver conditions.28 – 30 In 1989, our group reported results of a preliminary clinical trial suggesting that methotrexate may also have a role to play in refractory inflammatory bowel diseases.31 This study treated 14 patients with Crohn’s disease and 9 patients with chronic ulcerative colitis with 25 mg of parenteral methotrexate weekly for a 12-week study period. Approximately 75% of the patients in both groups had significant improvement as defined clinically and reduction in dose or elimination of corticosteroids. A subset of patients with Crohn’s disease had dramatic healing in colonic lesions as defined endoscopically and histologically. In contrast, no patient with ulcerative colitis showed endoscopic or histological remission. Furthermore, when followed up for approximately 18 months, only 40% of patients with chronic ulcerative colitis who went into clinical remission with parenteral therapy sustained that remission with 7.5–15 mg of oral methotrexate weekly.32 Since that initial report, there has been a paucity of additional trials using methotrexate for refractory or steroid-dependent inflammatory bowel disease. An openlabel study by Baron et al. used a gradually increasing dose, ultimately using 15 mg weekly for 15 weeks (2.5 mg, week 1; 5 mg, week 2; and 10 mg, week 3).33 Prednisone dosage for 10 patients with Crohn’s disease decreased from a mean of 37 { 9.6 to 8.3 { 2 mg/day (P õ 0.02). Six patients sustained a response (2 complete, 4 partial). In the 8 patients with chronic ulcerative colitis, the daily prednisone dose decreased from 26.3 { 3.2 to 12.7 { 2.0 mg/day (P õ 0.001), and 3 patients had a partial clinical response. Drug-related side effects were considered mild. Chamiot-Prieur et al. treated 39 patients with refractory Crohn’s disease for 12 weeks with 25 mg of parenteral methotrexate weekly followed by a tapering oral dose.34 Clinical remission at 1, 3, and 6 months was 53%, 72%, and 72%, respectively (life table analysis). Mean prednisone dose was 20.4 mg at the study initiation and 7.5 mg (P õ 0.05) at 6 months. Minor side effects were common (gastrointestinal symptoms, vertigo, and headache; 56%) but necessitated drug discontinuation in only 4 patients. Seventy-five percent of the patients had discontinued methotrexate within 18 months because of recurrent symptoms, noncompliance (13%), toxicity (10%), or sustained remission (5%). Before the study by Oren et al.35 reported in this issue of GASTROENTEROLOGY, there have been only two controlled trials using methotrexate for refractory in/ 5e0d$$0054
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flammatory bowel disease, both for Crohn’s disease. In one, Arora et al. administered methotrexate, 5 mg orally three times weekly, or placebo for 52 weeks to steroiddependent patients with Crohn’s disease followed by an attempt at steroid tapering.36 Fifty-four percent of patients in the methotrexate group remained in remission opposed to 20% in the placebo group (P Å 0.06). Feagan et al., in turn, treated 141 steroid-dependent patients with either placebo (n Å 47) or 16 weeks of 25 mg of weekly methotrexate (n Å 94).37 Approximately twice as many methotrexate-treated patients entered remission (39.4% vs. 19.1%; P Å 0.03) despite cessation of steroids. The patients receiving the active drug had a significantly lower Crohn’s Disease Activity Index (162 { 12 vs. 204 { 17; P Å 0.002) and received less prednisone overall (P Å 0.026). Seventeen percent of patients receiving the active drug were withdrawn from treatment for adverse events (6 with nausea, 7 with asymptomatic liver function test elevations) vs. 2% in the placebo group. This multicenter group is currently enrolling patients in a long-term placebo-controlled trial to determine the efficacy of 15 mg of oral methotrexate weekly on remission maintenance. From the standpoint of science, the report by Oren et al.35 is a well-done study. It is the first controlled trial using methotrexate for chronic ulcerative colitis. Randomizing 67 patients with active disease who had required either immunosuppressives or ¢5 mg of prednisone for 4 of the preceding 12 months to groups receiving either placebo (n Å 37) or 12.5 mg of oral methotrexate weekly (n Å 30), the authors showed a virtually identical response for the two groups after 9 months of treatment. This included proportion of patients entering first remission (approximately 50%), time to reach the first remission (3–4 months), and subsequent relapse (methotrexate, 64%; placebo, 44%; P Å NS). The mean Mayo Clinic score (composite of degree of bleeding, stool frequency, sigmoidoscopic findings, and physicians’ global assessment [remission defined °3, relapse ¢3 points]) were comparable, as were monthly steroid dose and abnormal laboratory study findings. Approximately two-thirds of both groups were receiving steroids and/or mesalamine products at study initiation, whereas the placebo-treated group was less likely to have received previous immunosuppressive agents (17% vs. 34%). There were 9 dropouts in the placebo-treated patients vs. 2 (P Å 0.052) in patients receiving methotrexate. The authors concluded that a weekly dose of 12.5 mg of methotrexate was ineffective in treating chronic active ulcerative colitis. This is a well-presented paper, and the statistical power of the study to detect a 30% difference between the two groups was 98.6%. Unfortunately, it leaves many WBS-Gastro
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questions unanswered. The easy one is: where was the toxicity in patients receiving the active drug? In my practice and in the previously mentioned studies,31 – 34,36,37 initiation of oral methotrexate in the doses used engenders nausea and a 24-hour exacerbation of diarrhea in up to a quarter of patients. These side effects are often minimized by initiation with parenteral therapy, whereas transaminase level elevations and the number of occasional cases of alopecia, stomatitis, and skin rash are comparable. At any rate, data in the rheumatologic literature clearly show that folic acid supplementation minimizes some of methotrexate’s side effects without changing drug efficacy.38 As such, and in contrast to the current study, all patients treated with methotrexate in our unit now receive concomitant folic acid supplementation.39 Was the dose chosen the correct one? Although this clearly requires further study both in chronic ulcerative colitis and Crohn’s disease, one wonders whether the paucity of side effects in the current study has any relationship to lack of response. In the 16-week study by Feagan et al., side effects in the 94 patients receiving 25 mg of the active drug included abnormalities in liver function test results (5%), nausea (4%), skin rash (1%), and pneumonitis (1%).37 I know of no study that has examined whether patients who developed side effects were more likely to have a clinical response. At least some of methotrexate’s side effects are idiosyncratic (e.g., hypersensitivity and pneumonitis), are related to concomitant drugs (alcohol or trimethoprimsulfamethoxazole), or are a consequence of cumulative dose (hepatic fibrosis).40,41 My experience in chronic ulcerative colitis suggests that doses õ20–25 mg weekly are unlikely to induce remission, and it is unusual in my practice to maintain a remission in chronic ulcerative colitis with õ15 mg weekly. Higher doses have also been shown to be effective in patients with resistant rheumatoid arthritis.42 Was the route of administration appropriate? Data show that methotrexate blood levels and bioavailability are reasonably comparable in most patients whether the drug is given orally or parenterally.43 – 46 The problem with using plasma levels, however, is that they bear no relation to clinical response when using low-dose therapy. This has been shown repeatedly in the rheumatologic literature and was also suggested by our original study.31 Parenteral methotrexate seems to be more effective in our experience and minimizes many of the gastrointestinal side effects noted with oral therapy. In my practice, approximately one-third of patients with Crohn’s disease treated with methotrexate are maintained on parenteral therapy (mean dose, 15 mg) either because of intolerance / 5e0d$$0054
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or relapse on initiation of oral therapy.32 This also deserves additional study. What is the long-term toxicity? Long-term toxicity should be zero for an ineffective drug. In other words, the drug should not be used. Assuming that there remain unanswered questions in both Crohn’s disease and chronic ulcerative colitis and that there is room for additional study, what can be said about prolonged methotrexate therapy? There are numerous reports in the dermatologic and rheumatologic literature showing that liver toxicity (fibrosis, cirrhosis) is a potential problem. Whereas the latter is uncommon in rheumatoid arthritis (approximately 1%),47 an incidence approximating 7% has been defined by meta-analysis when the drug is administered for psoriasis.48 Baseline abnormal liver function test results, concomitant alcohol use, a history of obesity or diabetes, daily administration of the drug, and a cumulative dose in excess of 1500 mg are all risk factors.41 Our unit currently interdicts alcohol absolutely and recommends liver biopsy at 1500, 3000, and 5000 mg. To date, no significant hepatopathology has been noted.49 Two other adverse events deserve mention with long-term therapy: hypersensitivity pneumonitis and bone marrow suppression. Whereas the latter can occur in up to a quarter of methotrexate-treated patients, most cytopenias are mild, reversible, and treated either by maintaining or reducing the dose.10,50,51 Patients who become folic acid depleted, those with renal insufficiency, or those taking simultaneous trimethoprim/sulfamethoxazole may occasionally develop profound suppression requiring leucovorin rescue and temporary drug discontinuation.42 Hypersensitivity pneumonitis, in turn, may be subtle, presenting with mild shortness of breath and a nonproductive cough or as fulminant pulmonary failure.53 Recognition is imperative and may require chest radiography, arterial blood gas measurements, pulmonary function studies to include carbon monoxide diffusing capacity, and even bronchoscopy with alveolar lavage. Occurring at any time during the course of therapy, treatment consists of methotrexate withdrawal, initiation of high-dose corticosteroid therapy, and occasionally ventilatory support.46 The randomized study by Oren et al.35 offers new insights into methotrexate use for inflammatory bowel disease. It is clear from the study that the drug has little to offer for chronic ulcerative colitis (not even toxicity) in the dose and route of administration selected. I await with interest the authors’ parallel study looking at a similar dosing regimen for refractory Crohn’s disease. Given previously published controlled studies showing clinical response to methotrexate for Crohn’s disease,31,32 lack of efficacy in this soon-to-be-completed study may WBS-Gastro
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imply an inadequate dose or route of administration. Efficacy, in turn, would at a minimum define discordant responses of the two disease processes to methotrexate. RICHARD A. KOZAREK
Section of Gastroenterology Virginia Mason Medical Center Seattle, Washington
References 1. Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pastenack BS. Treatment of Crohn’s disease with 6-mercaptopurine. A longterm, randomized, double-blind study. N Engl J Med 1980;302: 981–987. 2. Hawthorne AB, Logan RFA, Hawkey CJ, Foster PN, Axon AT, Swarbrick ET, Scott BB, Lennard-Jones JE. Randomized controlled trial of azathioprine withdrawal in ulcerative colitis. Br Med J 1992; 305:20–22. 3. Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S. Cyclosporin in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330: 1841–1845. 4. Kozarek RA. Review article: immunosuppressive therapy for inflammatory bowel disease. Aliment Pharmacol Ther 1993;7: 117–123. 5. Kornbluth A, George J, Sachar DB. Immunosuppressive drugs in Crohn’s disease. Gastroenterologist 1994;2:239–246. 6. Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: azathioprine; 6-mercaptopurine, cyclosporine, and methotrexate Am J Gastroenterol 1996;91:423– 433. 7. Seeger DR, Cosulich DB, Smith JM, Hultquist ME. Analogs of pteroylglutamic acid. 4-Amino derivatives. J Am Chem Soc 1949; 71:1753–1758. 8. White JC, Loftfield S, Goldman ID. The mechanism of action of methotrexate. III. Requirement of free intracellular methotrexate for maximal suppression of [14C]formate incorporation into nucleic acids and protein. Mol Pharmacol 1975;11:287–297. 9. Christophidis N. Methotrexate. Clin Rheum Dis 1984;10:401– 415. 10. Bleyer WA. The clinical pharmacology of methotrexate. New applications of an old drug. Cancer 1978;41:36–57. 11. Jolivet J, Cowan KH, Curt GA, Clendeninn NJ, Chabner BA. The pharmacology and clinical use of methotrexate. N Engl J Med 1983;309:1094–1104. 12. Segal R, Yaron M, Tartakovsky B. Methotrexate: mechanism of action in rheumatoid arthritis. Semin Arthritis Rheum 1990;20: 190–199. 13. Rosenthal GJ, Weigand GW, Germolec DR, Blank JA, Luster MI. Suppression of B cell function by methotrexate and trimetrexate. Evidence for inhibition of purine biosynthesis as a major mechanism of action. J Immunol 1988;141:410–416. 14. Brody M, Bohm I, Bauer R. Mechanism of action of methotrexate: experimental evidence that methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells. Eur J Clin Chem Clin Biochem 1993;31:667–674. 15. Weinstein GD, Jeffes E, McCullough JL. Cytotoxic and immunologic effects of methotrexate in psoriasis. J Invest Dermatol 1990;95:49S–52S. 16. Calabrese LH, Taylor JV, Wilke WS, Segal AM, Valenzuela R, Clough JD. Response of immunoregulatory lymphocyte subsets to methotrexate in rheumatoid arthritis. Cleve Clin J Med 1990; 57:232–241. 17. Kremer JM. The mechanism of action of methotrexate in rheumatoid arthritis: the search continues (editorial). J Rheumatol 1994; 21:1–5.
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18. Cronstein BA, Eberle MA, Gruber HA, Levin RI. Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. Proc Natl Acad Sci USA 1991;88:2441– 2445. 19. Nesher G, Moore TL. Effect of methotrexate on chemotaxis and superoxide production of normal monocytes. Arthritis Rheum 1989;32:S60. 20. Leroux JL, Damon M, Chavis C, Crastes de Paulet A, Blotman F. Effects of a single dose of methotrexate on 5- and 12-lipoxygenase products in patients with rheumatoid arthritis. J Rheumatol 1992;19:863–866. 21. Cronstein BN. Molecular mechanism of methotrexate action in inflammation. Inflammation 1992;16:411–423. 22. Sperling RI, Benincaso AI, Anderson RJ, Coblyn JS, Austen KF, Weinblatt ME. Acute and chronic suppression of leukotriene B4 synthesis ex vivo in neutrophils from patients with rheumatoid arthritis beginning treatment with methotrexate. Arthritis Rheum 1992;35:376–384. 23. Hanno R, Gruber GG, Owen LG, Callen JP. Methotrexate in psoriasis. A brief review of indications, usage, and complications of methotrexate therapy. J Am Acad Dermatol 1980;2:171–174. 24. Kremer JM, Phelps CT. Long term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis. Update after a mean of 90 months. Arthritis Rheum 1991;35:138–145. 25. Owen ET, Cohen ML. Methotrexate in Reiter’s disease. Ann Rheum Dis 1979;38:48–50. 26. Hoffman GS, Leavitt RY, Kerr GS, Fauci AS. The treatment of Wegener’s granulomatosis with glucocorticoids and methotrexate. Arthritis Rheum 1992;35:1322–1329. 27. Mullarkey MF, Blumenstein BA, Andrade WP, Bailey GA, Olason I, Wetzel CE. Methotrexate in the treatment of corticosteroiddependent asthma. A double-blind crossover study. N Engl J Med 1988;318:603–607. 28. Kaplan MM, Knox TA. Treatment of primary biliary cirrhosis with low-dose weekly methotrexate. Gastroenterology 1991;101: 1332–1336. 29. 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. 30. Knox TA, Kaplan MM. A double-blind, controlled trial of oral pulse methotrexate therapy in the treatment of primary sclerosing cholangitis. Gastroenterology 1994;106:494–499. 31. Kozarek RA, Patterson DJ, Gelfand MD, Botoman VA, Ball TJ, Wilske KR. Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989;110:353–356. 32. Kozarek RA, Patterson DJ, Gelfand MD, Ball T Jr, Botoman VA. Long-term use of methotrexate in inflammatory bowel disease: severe disease 3, drug therapy 2, seventh inning stretch (abstr). Gastroenterology 1992;702:A648. 33. Baron TA, Truss CD, Elson CO. Low-dose oral methotrexate in refractory inflammatory bowel disease. Dig Dis Sci 1993;38: 1851–1856. 34. Chamiot-Prieur C, Le´mann M, Mesnard B, Halphen M, Messing B, Modigliani R, Rambaud JC, Gendre JP, Gue´don C, Colombel JF. Treatment of refractory Crohn’s disease with methotrexate (abstr). Gastroenterology 1993;104:A680. 35. Oren R, Arber N, Odes S, Moshkowitz M, Keter D, Pomeranz I, Ron Y, Reisfeld I, Broide E, Lavy A, Fich A, Eliakim R, Patz J, Bardan E, Villa Y, Gilat T. Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial. Gastroenterology 1996;110:1416–1421. 36. Arora S, Katkov WN, Cooley J, Kemp A, Shapiro RA, Kelsey PB, Podolsky DK. A double-blind, randomized, placebo-controlled trial of methotrexate in Crohn’s disease (abstr). Gastroenterology 1992;102:A591. 37. Feagan BG, Rochon J, Fedorak RN, Irvine EJ, Wild G, Sutherland,
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L, Steinhart AH, Greenberg GR, Gillies R, Hopkins M. Methotrexate for the treatment of Crohn’s disease. N Engl J Med 1995; 332:292–297. Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, Koopman WJ, Krumdieck CL, Alarcom GS. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med 1994; 121:833–841. Kozarek RA. Methotrexate for refractory Crohn’s disease: preliminary answers to definitive questions (editorial). Mayo Clin Proc 1996;71:104–105. Goodman TA, Polisson RP. Methotrexate: adverse reactions and major toxicities. Rheum Dis Clin North Am 1994;20:513–528. Egan LJ, Sandborn WJ. Methotrexate for inflammatory bowel disease: pharmacology and preliminary results. Mayo Clin Proc 1996;71:69–80. Furst DE, Koehnke R, Burmeister LF, Kohler J, Cargill I. Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. J Rheumatol 1989;16:313–320. Teresi ME, Crom WR, Choi KE, Mirro J, Evans WE. Methotrexate bioavailability after oral and intramuscular administration in children. J Pediatr 1987;110:788–792. Zimmerman J. Methotrexate transport in the human intestine: evidence for heterogeneity. Biochem Pharmacol 1992;43:2377– 2383. Lebbe C, Beyeler C, Gerber NJ, Reichen J. Intraindividual variability of the bioavailability of low dose methotrexate after oral administration in rheumatoid arthritis. Ann Rheum Dis 1994;53:475– 477. Moshkowitz M, Oren R, Tishler M, et al. The absorption of lowdose methotrexate in patients with inflammatory bowel disease. Dig Dis Sci (in press). Kremer JM, Alarcon GS, Lightfoot RW Jr, Wilkens RF, Furst DE,
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Williams HJ, Dent PB, Weinblatt ME. Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. Arthritis Rheum 1994;37:316–328. Newman M, Auerbach R, Feiner H, Holzman RS, Shupack J, Migdal P, Culubret M, Camuto P, Tobias H. The role of liver biopsies in psoriatic patients receiving long-term methotrexate treatment: improvement in liver abnormalities after cessation of treatment. Arch Dermatol 1989;125:1218–1224. Kozarek RA, Bredfeldt JE, Rosoff LE, Patterson DJ, Fenster LF. Does chronic methotrexate cause liver toxicity when used for refractory inflammatory bowel disease (abstr)? Gastroenterology 1991;100:A221. Alcaron GS, Tracy IC, Blackburn WD Jr. Methotrexate in rheumatoid arthritis: toxic effects as the major factor in limiting longterm treatment. Arthritis Rheum 1989;32:671–676. Schnabel A, Gooss WL. Low-dose methotrexate in rheumatic diseases—efficacy, side effects and risk factors for side effects. Semin Arthritis Rheum 1994;23:310–327. Tishler M, Caspi D, Fishel B, Yaron M. The effects of leucovorin (folinic acid) on methotrexate therapy in rheumatoid arthritis patients. Arthritis Rheum 1988;31:906–908. Hargreaves MR, Mowat AG, Benson MK. Acute pneumonitis associated with low dose methotrexate treatment for rheumatoid arthritis: report of five cases and review of published reports. Thorax 1992;47:628–633.
Address requests for reprints to: Richard A. Kozarek, M.D., Section of Gastroenterology, Virginia Mason Medical Center, 1100 Ninth Avenue, P.O. Box 900 (C3-GAS), Seattle, Washington 98111. Fax: (206) 223-6379. 䉷 1996 by the American Gastroenterological Association 0016-5085/96/$3.00
The Role of Mast Cells in Gastrointestinal Inflammation See article on page 1482.
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linically, allergen-induced reactions are characterized by a biphasic response.1 Within minutes of exposure to an allergen, there is an immediate reaction, initiated by cross-linkage of specific immunoglobulin (Ig) E bound to high-affinity receptors (FceRI) on the surface of mast cells and basophils. The early reaction usually fades within 90 minutes but may be followed by a recurrence of symptoms several hours later. This socalled late-phase reaction is associated with a sustained inflammatory response, involving tissue infiltration by granulocytes and mononuclear cells. Allergic inflammation has been shown to be a component of allergic reactions in the skin, respiratory tract, and other tissues. Furthermore, it is generally accepted that recruited leukocytes present in the target tissue are key players in the pathogenesis of chronic allergic diseases. However, the / 5e0d$$0054
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participation of late-phase reactions in allergic gastrointestinal phenomena is unknown. In this issue, Wershil et al.2 show for the first time that pathological hallmarks of late-phase responses also occur during the course of an IgE-dependent reaction in the mouse stomach. Another important accomplishment of this study is the demonstration that allergic gastric inflammation is mast cell–dependent. The mast cell dependency was confirmed by examining the gastric reaction in mast cell–deficient W/Wv mice and W/Wv mice that had undergone selective reconstitution of gastric mast cell populations by the injection of bone marrowderived mast cells into the stomach wall. Whereas mast cell–deficient mice did not show IgE-dependent gastric inflammation, the gastric-reconstituted W/Wv mice developed a neutrophilic response that was similar to that of normal congenic mice. This finding was not entirely unexpected because previous studies have shown that mast cell degranulation can promote leukocyte infiltraWBS-Gastro