Methotrexate in IBD–move over 6-MP? Not so fast

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SELECTED SUMMARIES Henry J. Binder, M.D. Selected Summaries Editor Yale University School of Medicine New Haven, Connecticut

STAFF OF CONTRIBUTORS Laurence Blendis, Tel-Aviv, Israel Robert Bresalier, Detroit, MI Russell D. Cohen, Chicago, IL Glenn T. Furuta, Boston, MA William L. Hasler, Ann Arbor, MI Sreenivasa Jonnalagadda, St. Louis, MO Cyrus Kapadia, New Haven, CT

Saul J. Karpen, Houston, TX Ronald L. Koretz, Sylmar, CA Kris V. Kowdley, Seattle, WA James D. Lewis, Philadelphia, PA Gary R. Lichtenstein, Philadelphia, PA Douglas B. Nelson, Minneapolis, MN Richard M. Peek, Nashville, TN

BACLOFEN EFFECTS ON ESOPHAGEAL FUNCTION: A POSSIBLE THERAPY FOR GERD? Zhang Q, Lehmann A, Rigda R, Dent J, Holloway RH (Royal Adelaide Hospital, Adelaide, Australia). Control of transient lower oesophageal sphincter relaxations and reflux by the GABAB agonist baclofen in patients with gastro-esophageal reflux disease. Gut 2002;50:19 –24. Current therapy of gastroesophageal reflux disease (GERD) relies on medications to reduce acid secretion and surgical and endoscopic interventions to increase the barrier function of the gastroesophageal junction when drugs are inadequate. Pharmaceutical agents acting on diverse receptor subtypes have shown promise in decreasing the occurrence of transient lower esophageal sphincter relaxations (TLESRs), which are felt to underlie many acid reflux events. In the present investigation, Zhang et al. tested the physiologic effects of the ␥-aminobutyric acidB (GABAB) receptor agonist on esophageal function in patients with esophagitis. Twenty patients (15 men, median age 56 years) including 13 with Hetzel grade 2, 5 with grade 3, and 2 with grade 4 esophagitis were recruited into this study. Medications that affect gastrointestinal motility or acid secretion were discontinued at least 4 days before testing. After overnight fasting, patients were given baclofen 40 mg or placebo in random order. Sixty minutes later, a pH probe was placed with its tip 5 cm above the lower esophageal sphincter (LES), and a manometric assembly including a reverse-perfused sleeve sensor to span the LES was passed. Primary peristalsis was measured after 10 water swallows and secondary peristalsis was tested with 5 air boluses injected into the midesophagus. Patients then ingested 3000 kJ meals, manometry and pH recordings were obtained for 3 hours, and primary and secondary peristalsis were reassessed. Baclofen administration elicited a number of changes in esophageal function. There were 101 acid reflux episodes after baclofen vs. 174 after placebo. Postprandial reflux events decreased from 7.0 to 4.0 per 3 hours for each patient. Beginning 90 minutes after drug administration, baclofen produced in-

G. S. Raju, Galveston, TX Don C. Rockey, Durham, NC Fergus Shanahan, Cork, Ireland Nicholas J. Shaheen, Chapel Hill, NC Brad Warner, Cincinnati, OH David C. Whitcomb, Pittsburgh, PA Stephen D. Zucker, Cincinnati, OH

creases in fasting and postprandial LES pressure (7.9 ⫾ 0.3 and 5.8 ⫾ 0.6 mm Hg) vs. placebo (4.6 ⫾ 0.3 and 4.1 ⫾0.7 mm Hg). Baclofen markedly reduced the rate of TLESRs from a median of 15 (13.8 –18.3) to 9 (5.8 –13.3) per 3 hours (P ⬍ 0.0002). Baclofen decreased the total number of reflux episodes occurring during TLESRs by 44% but did not affect the fraction of TLESRs associated with acid reflux or with esophageal common cavities. There also was a significant reduction in the number of reflux episodes during periods of absent LES tone. Despite these beneficial effects, baclofen did not decrease the time that esophageal pH was ⬍4 nor did it affect esophageal acid clearance. Baclofen had no effect on primary or secondary esophageal peristalsis. The drug produced no appreciable side effects; however, plasma growth hormone levels increased 2–3 hours after dosing. To conclude, the GABAB receptor agonist baclofen inhibits acid reflux episodes by reducing TLESRs and, to a lesser degree, by increasing LES tone. On the basis of these findings, the investigators suggest that GABAB agonists may be useful agents for the treatment of gastroesophageal reflux disease. Comment. The most commonly used medications to treat gastroesophageal reflux disease (GERD) act via inhibition of gastric acid secretion rather than addressing the underlying pathophysiology of the disorder. Transient lower esophageal sphincter relaxations (TLESRs), defined as LES pressures ⱕ2 mm Hg not associated with swallows and with relaxation rates ⱖ1 mm Hg/second and times from onset to complete relaxation of ⱕ10 seconds, have been demonstrated to underlie many reflux events into the esophagus (Am J Physiol 1995;268:G128 –G133). TLESRs are associated with acid reflux in patients with GERD, but promote reflux of nonacidic liquids in healthy volunteers (Am J Gastroenterol 2001;96:647– 655, Dig Dis Sci 2000;45:1293–1300). In a study of 67 GERD patients, TLESRs accounted for 82% of reflux episodes (Gut 1988;29:1020 –1028). In those with greater degrees of esophagitis, absent LES tone was more important, accounting for 23% of reflux events. Esophagitis also is associated with impaired esophageal motility during TLESRs (Dig Dis Sci 2000;45:1293–1300). Finally, TLESRs lead to development of common cavities, which facilitate retrograde liquid movement from the stomach into the esophagus (Neurogastroenterol Motil 1996;8:131–141). TLESRs are vagally mediated phenomena that result from a variety of mechanical and neurohumoral factors (Aliment Pharmacol Ther 2002;16:17–26). Meals provoke 4-fold increases in TLESRs in GERD

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patients (Dig Dis Sci 1991;36:1034 –1039). Meal-induced TLESRs are blocked by pretreatment with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine, showing involvement of nitrergic pathways (Dig Dis Sci 2000;45:2069 –2075). Meal effects on the LES are mimicked by gastric distention, suggesting a mechanical component to TLESR induction (Gastroenterology 1998;115:1374 –1380). TLESRs elicited by gastric distention with liquid are longer in duration than those induced by air inflation, emphasizing their importance in acid reflux (Neurogastroenterol Motil 1999;11:125–132). Cholecystokinin (CCK) induces TLESRs by itself and increases the rate of TLESRs evoked by gastric distention (Gut 1997;40:575–581, Am J Physiol 2001;281:G350 –G356). Prokinetic drugs have been used to treat GERD by increasing LES pressure. Cisapride was effective in nocturnal reflux via its actions on the LES (Med Lett 1994;36:11–13). Other agents have been proposed as potential GERD therapies based on their purported capabilities to increase the barrier function of the LES; however, each has significant drawbacks. The 5-HT1 receptor agonist sumatriptan increases postprandial LES tone in healthy volunteers, but unfortunately elicits TLESRs as a consequence of its relaxant actions on the gastric fundus (Am J Gastroenterol 1999;94:3158 –3164). Morphine reduces TLESRs and decreases esophageal acid exposure and the number of reflux episodes in GERD patients but has issues regarding effects on mentation and drug dependency (Gastroenterology 1997;113: 409 – 414). The muscarinic receptor antagonist atropine reduces TLESRs in healthy volunteers and GERD patients, decreases the number of reflux episodes, and blocks TLESRs in response to gastric distention (Gut 2000;47:30 –36, Gut 1998;43:12–16, Gut 1997;41:285–290). However, atropine also decreases LES pressure, making this drug class less attractive (Gastroenterology 1995;109: 1547–1554, Gut 1998;43:12–16). The CCKA receptor antagonist loxiglumide decreases TLESRs, reflux episodes, and esophageal acid exposure in healthy volunteers; however, it also delays gallbladder emptying, raising concern about a predisposition to promoting gallstone formation (Am J Gastroenterol 1998;93:1823– 1828, Gastroenterology 1998;115:597– 604). Because of its beneficial actions on the LES and stomach, the GABAB receptor agonist baclofen has received attention as a possible treatment for GERD. GABAB receptors are prominent in brainstem vagal nuclei and on preganglionic neurons projecting to the LES (Gastroenterology 2001;120:1749–1762). Effects of baclofen on gastric contractions are blocked by vagotomy and atropine, indicating action on vagal cholinergic pathways ( J Phyiol 1987;388:25–39). Baclofen also reduces responses of gastroesophageal afferent fibers to mucosal stroking and to circumferential tension, thereby demonstrating modulation of peripheral mechanosensory endings by GABAB receptor occupation ( J Neurosci 1999;19:8597– 8602). In animal studies pertinent to GERD pathogenesis, baclofen has been shown to reduce TLESRs while GABAB receptor agonists that do not cross the bloodbrain barrier are without effect showing the importance of central neural actions (Am J Physiol 1999;277:G867–G874, Gastroenterology 1999;117:1147–1154). Most recently in healthy humans, baclofen was observed to reduce the rate of gastroesophageal reflux episodes by 60% via decreases in TLESRs and increases in basal LES pressure (Gastroenterology 2000;118:7–13). In the current investigation, Zhang et al. extend these observations to patients with endoscopic evidence of esophagitis. Baclofen impressively reduced the rate of TLESRs, significantly increased both fasting and postprandial LES pressure, and decreased the number of reflux events attributable to TLESRs or absent LES tone. It is reasonable to postulate that these physiologic effects could produce improvements

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in symptoms of gastroesophageal reflux. The inability of this research to demonstrate reductions in esophageal acid exposure is not a weakness of this investigation. Rather, it likely is a function of a protocol design in which esophageal pH was measured for only 3 postprandial hours. The effects of baclofen on esophageal pH would be better assessed by monitoring over a 24-hour period, including fasting and nocturnal values. Might baclofen become a viable option in the management of GERD? Performance of a prolonged, placebo-controlled symptom assessment trial would help answer this question. However, enthusiasm over the findings of the current investigation must be tempered by several concerns about the drug. Under some experimental conditions, baclofen increases gastric acid secretion (Br J Pharmacol 1986;89:461– 467, Dig Dis Sci 1990;35:458 – 466, Life Sci 2001;68: 1951–1963). If such a physiologic response develops in GERD patients, it could counteract any beneficial effects on esophagogastric motor function. Furthermore, the side effect profile of baclofen is worrisome. A single 40-mg dose was used in the current study to measure the drug’s acute effects on distal esophageal function. However, chronic administration of baclofen limits drug dosing to 20 mg 4 times a day. At that dose, neurologic toxicity is significant with prominent sedation, dizziness, and weakness. Gastrointestinal symptoms such as nausea, vomiting, and constipation also are observed. More importantly, patients who abruptly discontinue baclofen therapy after prolonged use may experience hypotension, paranoia, hallucinations, or seizures. Thus, for a disorder in which medications commonly are taken only when symptoms are severe, gastroenterologists and primary physicians would need to provide careful prescription instructions to affected patients. If these issues are resolved during clinical testing, in what settings might a drug like baclofen be indicated? Patients incompletely responsive to high-dose proton pump inhibitor therapy might derive benefit from a medication such as baclofen, which acts via a distinct physiologic mechanism. Those individuals who experience pyrosis and other symptoms as a consequence of gastroesophageal reflux of nonacidic liquids also might be expected to improve on a drug that increases the barrier function of the LES. Although this is conceptually attractive, reflux of nonacidic fluids tends to correlate closely with acid reflux in patients with intact upper gastrointestinal anatomy (Gastroenterology 1996;111:1192–1196). Thus, the population that might benefit from this action of baclofen would be restricted to those patients who have undergone prior gastric resection or vagotomy and who now experience bilious esophageal reflux. Perhaps the most compelling impetus to consider a GABAB receptor agonist in the treatment of GERD would be to contain the significant expenses associated with proton pump inhibitor therapy. If shown to be safe and effective, a drug such as baclofen costing less than $1 per day would be desirable in a health care environment in which acid suppressive medications costing more than $4 a dose are restricted by providers. WILLIAM L. HASLER, M.D.

METHOTREXATE IN IBD – MOVE OVER 6-MP? NOT SO FAST. . . Fraser AG, Morton D, McGovern D, Travis S, Jewell DP. (Department of Medicine, University of Auckland, Auckland, New Zealand; John Radcliffe Hospital, Oxford; and Gastroenterology Unit, University of Oxford, Oxford, England). The

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efficacy of methotrexate for maintaining remission in inflammatory bowel disease. Aliment Pharmacol Ther 2002;16:693– 697. Patients with steroid-dependent or steroid-refractory Crohn’s disease or ulcerative colitis have been increasingly treated with the purine analogues 6-mercaptopurine and azathioprine. Data from a variety of sources have suggested that these agents are efficacious in the induction and maintenance of remission, and long-term safety with these agents has been promising (Gastroenterol Clin North Am 1989;18:57–71, Ann Intern Med 1995;123:132–142). Methotrexate, used primarily in Crohn’s disease, has often been delegated a “back-seat” to the purine analogues, for use only when the patient is allergic, intolerant, or nonresponsive to those agents. Reasons for methotrexate’s “second-class status” in inflammatory bowel disease (IBD) perhaps is due to the lack of long-term efficacy data and concerns of safety. Now, a recent multicenter retrospective review of methotrexate’s use in IBD suggests that physicians consider more expanded and, perhaps, preferential use of this agent (Aliment Pharmacol Ther 2002;16:693– 697). Notes were reviewed on 70 patients (42 female) with either Crohn’s disease (48) or ulcerative colitis (22) who were treated with methotrexate. Mean methotrexate dose was 20 mg (range, 10 –25), given orally (89%) or intramuscularly once weekly for a mean duration of 17 months (range, 0.5–71). “Remission” was defined as “lack of need for oral steroids for at least 3 months.” The addition of either steroids, infliximab, or referral for surgery was considered as indicators of “relapse.” The authors state that “most” of the patients had been treated with azathioprine, 35 of whom were intolerant. Efficacy data were reported only for the 55 patients (79%) who completed at least 3 months of methotrexate therapy; safety data were included for all patients. Remission was achieved in 62% of those completing at least 3 months of therapy (49% of the entire group). Details about these patients were not provided, other than mention of a logistic regression whereby methotrexate dose (but not diagnosis, disease site, joint symptoms or other extraintestinal symptoms, or age at either treatment or diagnosis) was predictive of remission. Remission maintenance while on methotrexate was 90%, 73%, and 51%, at 12, 24, and 36 months, respectively. Those who stopped methotrexate therapy did much worse, with values of 42%, 21%, and 16% at the same time periods. Safety data was surprisingly good, with side effects reported in 27%, leading to cessation of therapy in 19%. The most common adverse events were nausea and vomiting (10%), leukopenia (4%), infection (4%), diarrhea (3%), and stomatitis, elevated AST, and photosensitivity (all 1%). There was one death from multiorgan failure that could not be clearly linked with the drug. The investigators concluded that methotrexate is efficacious and safe in Crohn’s disease and ulcerative colitis, and is a

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“useful alternative” to the purine analogues that “may have comparable efficacy.” Comment. Methotrexate’s emergence into the IBD world has resulted in a foray of uncontrolled reports, reviews, and trials, as well as a few well-designed placebo-controlled studies of the drug’s efficacy and safety. All have been invaluable in contributing to our knowledge about this drug’s use and limitations. First, it would be helpful to differentiate the treatment of Crohn’s disease from that of ulcerative colitis with this agent. The lackluster results in ulcerative colitis have resulted in the near abandonment of this agent as a therapeutic choice for these patients. Previous published experiences in ulcerative colitis may have been plagued by the low dose or choice of oral delivery of this agent (Gastroenterology 1996;110:1416 –1421). The current study (Aliment Pharmacol Ther 2002;16:693– 697) does not provide the reader with enough separate data on the ulcerative colitis cohort (such as demographics, severity and location of disease, previous therapies, initial prednisone dose) to enable us at this time to reopen the medicine chest for this condition. Methotrexate’s use in Crohn’s disease, in contrast, has been repeatedly bolstered by a variety of published studies. Most notable are the multicenter, placebo-controlled trials that have established its role as an effective agent for the induction and maintenance of remission in Crohn’s disease. The first of these studies found remission and steroidwithdrawal rates of 39% in steroid-dependent Crohn’s patients, vs. 19% in placebo (N Engl J Med 1995;332:292–297). The benefit over placebo was only seen for those patients who were receiving ⱖ20 mg of prednisone daily at the initiation of the trial, suggesting either a synergistic benefit of using both agents, or a higher tendency for a “placebo-response” in patients who were already nearly off of prednisone. Data from our own open-label experience at the University of Chicago (Aliment Pharmacol Ther 2001;15:35– 44) also found a higher likelihood of improvement in those patients who were receiving concomitant corticosteroids (67% vs. 0%). Again, the current study does not provide the reader with enough information on steroid dosing to determine the role it might play in either the Crohn’s disease or ulcerative colitis patient groups. Methotrexate’s use as a maintenance agent in Crohn’s disease was confirmed by a second multicenter placebo-controlled trial, with relapse rates of 42% compared with 64% with placebo (N Engl J Med 2000;342:1664 –1666). The trial’s 40-week endpoint had left the need for further studies of the drug’s long-term maintenance record. Maintenance rates have varied greatly between open-label experiences. A French consortium study of 41 patients reported cumulative 1-, 2-, and 3-year relapse rates of 29%, 41%, and 48%, respectively (Am J Gastroenterol 2000;95:1730 –1734). A Belgian study of 20 steroidrefractory patients reported a disappointing 33% 12-month remission maintenance with methotrexate, although steroid-tapering was seen in 85%, with 60% discontinuing steroids completely at 6 months (Inflamm Bowel Dis 1999;5:11–15). Our published open-label experience (Aliment Pharmacol Ther 2001;15:35– 44) provided insight not only into long-term maintenance, but also on differences in efficacy dependent on drug delivery. Patients who received parenteral methotrexate (as was done in both of the placebo-controlled trials) had superior 12-, 14-, and 48-month remission maintenance rates (80%, 70%, and 47%, respectively) to the combined rates for patients receiving oral or parenteral dosing (75%, 31%, and 21%, at the same time points). Placebo-controlled experience with oral methotrexate has also failed to show a benefit versus placebo in maintenance of remission in Crohn’s disease (Am J Gastroenterol 1997;92:2203–2209). This benefit of parenteral dosing

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may be caused by its linear pharmacokinetics profile, compared with the highly variable oral bioavailability of the oral formulation (50%– 90%) (Ann Intern Med 1989;110:353–356, Mayo Clin Proc 1996; 71:69 – 80). It is difficult to determine what message to take from the current study. More detailed information about the patients’ disease and treatment course is needed, as well as separate results for ulcerative colitis and Crohn’s disease. Retrospective determinations of “remission” are difficult, and the current study’s use of the definition “a lack of need for oral steroids for at least 3 months” may be too vague and open to confounders such as patient refusal to restart steroids. As far as displacing 6-MP and azathioprine from the “top spot” for steroid-dependent or steroid-refractory disease, there is plenty of good data supporting the use of parenteral methotrexate for the induction and maintenance of remission in Crohn’s disease; its long-term safety is still concerning. The drug is underused in Crohn’s disease, especially in patients allergic or intolerant to the purine analogues. Patients with ulcerative colitis, however, will have to wait for larger prospective studies to justifying its use. RUSSELL D. COHEN, M.D.

NEW INSIGHTS INTO MICROBIALLY INITIATED GASTRIC MALIGNANCIES: BEYOND THE USUAL SUSPECTS Zavros Y, Rieder G, Ferguson A, Merchant JL (Howard Hughes Medical Institute and the Departments of Internal Medicine, Physiology, and Pathology, University of Michigan, Ann Ar bor, Michigan). Gastritis and hypergastrinemia due to Acinetobacter lwoffi in mice. Infect Immun 2002;70:2630 –2639. Gastric adenocarcinoma is the second leading cause of cancer-related death in the world, and 2 histologically distinct variants have been described. Diffuse-type gastric cancer most commonly affects younger persons, affects men and women equally, and consists of individually infiltrating neoplastic cells that do not form glandular structures (Gastroenterol Clin North Am 2000;29:579 –592). In contrast, intestinal-type gastric adenocarcinoma usually occurs at a later age, predominates in men, and progresses through a well-defined series of histologic steps (Gastroenterol Clin North Am 2000;29:579 – 592). This chain of events is initiated by the transition from normal mucosa to chronic superficial gastritis, which then leads to atrophic gastritis and intestinal metaplasia, and finally to dysplasia and adenocarcinoma (Cancer Epidemiol Biomarkers Prev 1996;5:477– 481). Helicobacter pylori is the strongest known risk factor for intestinal-type gastric cancer, and longterm interactions between H. pylori and its host also significantly increase the risk for precursor lesions such as atrophic gastritis and intestinal metaplasia (Nature Reviews Cancer 2002;2:28 –37). However, only a small percentage of H. pylori– colonized persons ever develop neoplasias related to its presence, and recent data indicate that microbial:host interactions that are governed by differences in genotype act in conjunction with permissive environmental conditions to collectively determine cancer risk (Nature Reviews Cancer 2002; 2:28 –37).

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A histologic outcome of persistent H. pylori infection with physiologic consequences is the development of atrophic gastritis with hypochlorhydria, which permits overgrowth of non-H. pylori acid-sensitive bacteria. Traditional dogma suggests that the mechanism through which polymicrobial colonization influences gastric cancer development is via conversion of ingested N-nitrosamines to carcinogenic nitrites (Cancer Epidemiol Biomarkers Prev 1996;5:477– 481). Recent investigations have explored the possibility that non–H. pylori bacterial colonization of the stomach may also replicate many of the physiologic derangements associated with H. pylori infection, with the implication being that gastric responses to the presence of bacteria are not specific for a particular species. Mice that are hypochlorhydric, as a result of either genetically induced gastrin deficiency or proton-pump inhibitor therapy, develop bacterial overgrowth and gastric inflammation, which is followed by an increase in the populations of G cells and parietal cells (Gastroenterology 2002;122:119 –133). In mice treated with proton-pump inhibitors, hypergastrinemia leads to a reduction in the quantity of somatostatin-producing D cells, and these findings can be replicated in hypochlorhydric gastrin-deficient mice that are exogenously infused with gastrin (Gastroenterology 2002;122:119 –133, Am J Physiol Gastrointest Liver Physiol 2002;282:G175–G183). Because alterations in the gastrin-somatostatin axis resolve after antibiotic therapy, gastric inflammation is likely to be the initiating event for these pathophysiological derangements (Gastroenterology 2002;122:119 –133, Am J Physiol Gastrointest Liver Physiol 2002;282:G175–G183). A bacterial genus that may directly contribute to induction of inflammation within a hypochlorhydric gastric niche is Acinetobacter. Acinetobacter are among the microbial populations that can be isolated from human and rodent stomachs with reduced acid outputs (Am J Respir Crit Care Med 1997;156: 1647–1655, Scand J Gastroenterol Suppl 1985;111:7–16, Scand J Gastroenterol 1984;19:355–364, Eur Respir J 1996; 9:1729 –1735). A specific outer membrane protein of one species of Acinetobacter, A. lwoffi, can activate the promoter regions of the proinflammatory cytokine interleukin 8 and gastrin in vitro, leading to the hypothesis that this species may be pivotal in initiating inflammation and hypergastrinemia in the setting of decreased acid output (Infect Immun 2000;68: 3657–3666). To this end, Zavros et al. directly compared the histologic and pathologic sequelae following monoinoculation with either A. lwoffi or H. pylori in a murine model of gastritis. Mice challenged with either H. pylori or A. lwoffi were killed 2, 3, and 4 months after infection. H. pylori reproducibly infected mice, as determined by culture and histology, and as predicted, inflammation and mucous gland metaplasia developed by 2 months after challenge. Of interest, A. lwoffi could not be cultured from gastric tissue specimens even though an inflammatory and injury response was induced. The mucosal presence of A. lwoffi was therefore determined by polymerase chain reaction coupled with restriction enzyme digestion of amplified products, and DNA specific for A. lwoffi was present in all mice challenged with this organism. Although the

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tempo and intensity of inflammation was slightly decreased in A. lwoffi–infected compared with H. pylori–infected mice, there were no differences in the severity of inflammation at 4 months after challenge. The authors then examined the types of inflammatory, neuroendocrine, and epithelial cell populations altered by experimental infection. Mucosal levels of T- and B-cell lymphocytes were increased in mice challenged with both bacterial species with no differences between the 2 groups. Infection with H. pylori or A. lwoffi led to similar increases in parietal cell mass and the number of cells positive for epidermal growth factor receptor, which served as a surrogate marker for epithelial cells. Antral G-cell mass also increased in both colonized groups, and this was accompanied by a corresponding reduction in the antral D cell population. Finally, hypergastrinemia developed in mice infected both with H. pylori and with A. lwoffi, and gastrin levels were not significantly different in the 2 groups. Comment. Although H. pylori is the strongest known risk factor for non-cardia gastric cancer, a subset of patients with gastric adenocarcinoma have no discernible evidence of pre-existing or current H. pylori infection (Ital J Gastroenterol Hepatol 1999;31:836 – 841). One possibility for this discrepancy is that detection of H. pylori in these patients is more difficult because colonization diminishes in the presence of premalignant lesions such as atrophic gastritis or intestinal metaplasia. Another explanation, which is not mutually exclusive, is that other bacterial species can induce or perpetuate inflammation when allowed to flourish in an environment unrestricted by acidity. Zavros et al. have previously reported that the murine gastric mucosal response to inflammation induced by non–H. pylori bacteria recapitulates the pattern of antral G-cell (increased) and D-cell (decreased) alterations originally identified in H. pylori–infected human subjects (Gastroenterology 2002;122:119 –133, Am J Physiol Gastrointest Liver Physiol 2002;282:G175–G183). Their current results examine this phenomenon in greater depth by directly comparing inflammation-induced alterations in neuroendocrine physiology that develop in response to A. lwoffi to those induced by H. pylori. Having established that there are no significant differences in any of the parameters measured, the authors conclude that in this model, gastritis and its sequelae are not specific to H. pylori. These experiments provide fresh insights regarding determinants that may influence gastric carcinogenesis, but as with all mechanistic studies, there are now new hypotheses to be explored. This group of investigators has previously shown that an outer membrane protein (OmpA-like protein) of A. lwoffi activates interleukin 8 and gastrin promoter activity in vitro. An extension of the current findings will be to determine if the mucosal derangements induced by wild-type A. lwoffi are decreased or absent after challenge with OmpA-deficient strains. Does infection with A. lwoffi beyond 4 months lead to gastric atrophy? What specific types of T-cell responses are induced by A. lwoffi? Helicobacter species induce a robust Th1-mediated response within human and murine gastric mucosa that is ineffective in eradicating the bacteria and that likely contributes to its long-term persistence within the gastric niche ( J Immunol 1996;156:4729 – 4738, Gastroenterology 1998;114:482– 492, Nat Med 2000;6:536 – 542). As the authors correctly point out, a Th1-type response can be initiated not only by viable bacteria but also by bacterial DNA alone through activation of the Toll-like receptor 9 (Nature 2000;408: 740 –745). Recent data have similarly indicated that H. pylori DNA

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per se is sufficient to stimulate production of the Th1-type cytokines interferon ␥ and interleukin 12 from peripheral blood mononuclear cells (Infect Immun 2000;68:6265– 6272). Because only A. lwoffi DNA was detected in mice challenged with this strain, interactions between inert microbial constituents and specific Toll-like receptors may be the underlying mechanism through which this organism induces gastric inflammation and injury. Finally, although mice are an ideal model that allows detailed analyses of host susceptibility to defined microbial species and pathological consequences, these findings should ultimately be extended into populations of human patients who may be at increased risk for gastric carcinogenesis on the basis of reduced acid secretory states. The results from Zavros et al. indicate, however, that the spectrum of bacteria that can induce gastric inflammation and injury responses with premalignant potential is an ever-expanding one. RICHARD M. PEEK, JR.

Reply. As pointed out by Dr. Peek, lower acid secretion could make the stomach hospitable for colonization by bacteria other than Helicobacter, yet induce similar if not identical histopathological changes. This places greater significance on the continued ability of the stomach to secrete acid. Helicobacter has evolved to bypass this ancient antimicrobial defense mechanism (Gastroenterology 1996;111:886 – 900, Science 2000;287:482– 485). Because most other organisms that we ingest are destroyed by gastric acidity, the stomach pH, in essence, regulates the type of bacterial flora that is able to colonize. Consistent with this notion, our findings showed a similar inflammatory response in the stomach regardless of the microbial culprit (Infect Immun 2002;70:2630 –2639, Gastroenterology 2002;122:119 –133), thus providing a possible explanation for the 25% of gastritis patients who are negative for Helicobacter (Ital J Gastroenterol Hepatol 1999;31: 836 – 841). Elevated gastrin levels observed during Helicobacter infection prompted us to explore why the feedback mechanism for acid secretion is not activated. Based on the prevalent dogma on acid secretion, one would predict that hyperacidity generated during the infection should inhibit gastrin secretion. Rather, what is observed is an increase in gastrin expression accompanied by hyperacidity (Gastroenterology 1991;100:1571–1575, Am J Gastroenterol 1994;89: 2033–2037). Coincidentally with the changes in acid secretion, hypergastrinemia also inhibits the somatostatin inhibitory pathway generating maximal gastric acid secretion (Am J Physiol Gastrointest Liver Physiol 2002;282:G175–G183). Thus, gastric acid secretion may be considered as an effective epithelial defense mechanism. This epithelial defense is reminiscent of the innate immune response that utilizes pathogen recognition receptors (toll-like receptors) on epithelial cells to identify molecules of microbial origin (Nature 2000;408: 740 –745, Infect Immun 2000;68:6265– 6272). Thus we propose that acid secretion is simply a tissue-specific arm of the innate immune system. Another conclusion that could be drawn from our study is that the presence of live bacteria is not always essential for triggering an inflammatory response. This is based on our inability to culture Acinetobacter from the stomachs despite persistent inflammation. This supports the idea that the mere presence of bacterial DNA is sufficient to trigger inflammation of the stomach (Nature 2000;408:740 –745, Infect Immun 2000;68:6265– 6272). Because persistent inflammation eventually leads to loss of the parietal cells and acid secretion, our results would suggest that a variety of organisms might predispose infected subjects to neoplastic transformation. Thus, we would reit-

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erate Dr. Peek’s comments that we should cast our net wider when considering the microbial trigger for neoplastic transformation. Human studies support the notion that Helicobacter’s niche narrows as the stomach loses its ability to secrete acid. Along these lines, perhaps we should revisit the impact that iatrogenic acid suppression may have over decades of chronic use. Although a connection with adenocarcinoma has not been observed with PPI use, our experience with these drugs is less than a generation old. Recent studies have shown a correlation between long-term acid suppressive therapy and formation of carcinogenic N-nitroso compounds (Gastroenterology 1997;112:A126, Gastroenterology 1999;116:813– 822, Eur J Gastroenterol 2000;12:165–173) serving to remind us to remain vigilant as we gain greater experience with the chronic use of these very efficient acid inhibitors. SIVAPRAKASH RATHINAVELU, PH.D. YANA ZAVROS, PH.D. JUANITA L. MERCHANT, M.D., PH.D.

ALL KIDDING ASIDE WITH THE USE OF LAMIVUDINE IN CHILDREN WITH CHRONIC HEPATITIS B Jonas MM, Kelley DA, Mizerski J, Badia IB, Areias JA, Schwarz KB, Little NR, Greensmith MJ, Gardner SD, Bell MS, Sokal EM for the Internal Pediatric Lamivudine Investigator Group (Children’s Hospital, Boston, Massachusetts; Diana Princess of Wales Hospital, Birmingham, United Kingdom; John Paul II Hospital, Krakow, Poland; Hospital de Nin˜os Ricardo Gutierrez, Buenos Aires, Argentina; Hospital Geral de Santo Antonio, Porto, Portugal; Johns Hopkins University, Baltimore, Maryland; GlaxoSmithKline, Research Triangle Park, North Carolina; GlaxoSmithKline, Greenford, United Kingdom; and Cliniques Universitaires St. Luc, Brussels, Belgium). Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med 2002;346:1706 –1713. Every time I give a child a drug that has not been tested in children I perform an uncontrolled experiment, and this is unacceptable. —Dr. Philip Walson (Nat Med 2000;6:1069) Children are not little adults. This fact is highlighted by the variable natural history of infection with the hepatitis B virus (HBV), which has been shown to be greatly influenced by the age at acquisition. While the risk of developing chronic HBV infection after an acute exposure is less than 10% in adults, it is 25%–30% in children under 5 years of age, and approximately 90% in untreated newborns of hepatitis B e antigen (HBeAg)-positive mothers (Hepatology 2001;34:1225–1241, N Engl J Med 1975;292:771–774). Patients with perinatally acquired infection frequently display immune tolerance, characterized by HBeAg positivity, high serum HBV DNA, and normal ALT levels (Dig Dis 1992;10:46 –52). Many of these children subsequently go on to develop elevated transaminases with HBeAg-positive chronic hepatitis and hepatocellular carcinoma later in life (Hepatology 1988;8:1130 –1133, Hepatology 1990;12:657– 660, Hepatology 1995;22:1387–1392).

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The carrier state for HBV is typically defined as the presence of hepatitis B surface antigen (HBsAg) in the serum for a minimum of 6 months. Hepatitis B carriers who acquired their infection in later childhood or as an adult exhibit spontaneous rates of HBeAg clearance approaching 80% by 10 years (Ann Intern Med 2001;135:759 –768, Gastroenterology 1990;99: 805– 810). On the other hand, this rate is substantially lower for neonatally acquired disease (Hepatology 1988;8:1130 – 1133, Hepatology 1995;22:1387–1392) as well as in immunosuppressed individuals (J Infect Dis 1989;160:577–582, Hepatology 1999;29;1306 –1310). Long-term follow-up studies of HBsAg-positive children indicate extremely slow clearance of HBsAg (0.6%/year) and low rates of surface antibody development (Hepatology 1992;15:380 –386). Although children with chronic HBV infection are usually asymptomatic, and hepatic injury during childhood is typically mild, severe liver damage has been shown to occur in a proportion of these patients (J Gastroenterol Hepatol 2000;15[suppl]:E16 –E19, Gastroenterology 1990;99:805– 810). Furthermore, it is estimated that adult HBV carriers who acquired their infection during childhood develop primary hepatocellular carcinoma at a rate of approximately 5% per decade, over 100 times that in uninfected individuals (Ann Intern Med 2001;135:835– 836). Based on these troubling statistics, treatment strategies for eradicating the virus in infected children seem prudent. Clearly, the best way to prevent HBV-induced liver disease is to avoid it altogether, through the application of universal vaccination. The hepatitis B vaccine is highly efficacious, with mass neonatal immunization programs showing a greater than 90% reduction in vertical transmission rates and a significantly lower incidence of hepatocellular carcinoma (Ann Intern Med 2001;135:796 – 800). However, vaccination programs do not solve the problem of what to do with a child who is already infected with HBV. Recombinant interferon ␣-2b (5 million U subcutaneously daily or 10 million U subcutaneously 3 times per week for 16 weeks) has been shown to induce HBeAg seroconversion in approximately 36% of adults with chronic HBV (N Engl J Med 1990;323:295–301), with longterm loss of HBsAg occurring in 20% (Ann Intern Med 1991;114:629 – 634). However, these responses occur on a background of a 12%–17% rate of spontaneous clearance of HBeAg in untreated carriers, and at the cost of frequent and significant untoward side effects (Ann Intern Med 2000;132: 723–731). More recently, lamivudine, a nucleoside analogue, has been found to induce loss of HBeAg after 1 year of treatment in 32% of patients compared with 11% of controls (N Engl J Med 1999;341:1256 –1263), with the majority exhibiting a durable response after discontinuation of treatment. Although the benign side-effect profile and oral administration of lamivudine compare favorably with interferon, the development of viral resistance is a frequent problem. Resistance is most commonly the result of mutations that develop at the YMDD locus of HBV, primarily because of the substitution of valine or isoleucine for methionine at amino acid residue 552 (Hepatology 1998;27:1670 –1677). YMDD mutations typically be-

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gin to emerge 6 months after initiation of treatment and increase in frequency with the duration of therapy, manifesting in 14%–32% of patients by 1 year (N Engl J Med 1999;341: 1256 –1263, N Engl J Med 1999;339:61– 68, J Viral Hepat 2001;270 –275, Hepatology 1999;30:1082–1087). Because many patients with YMDD mutations continue to demonstrate partial suppression of HBV DNA and improvement in both ALT levels and histologic findings, continued long-term therapy has been advocated despite the occurrence of viral breakthrough (Ann Intern Med 2001;132:723–731). Because of the more indolent natural history of chronic HBV in children, it is not intuitive that data regarding responses to treatment in adults can be extrapolated to pediatric populations. Although trials of interferon therapy in HBV-infected children suggest similar response rates (26%) to that observed in adults (Gastroenterology 1998;114:988 – 995), a long-term study reported nearly identical HBeAg clearance rates in treated patients (60%) vs. untreated control subjects (65%) at 5 years of follow-up (Gut 2000;46:715– 718). These findings suggest that interferon may simply be accelerating the natural clearance of HBV that would have occurred anyway in these patients. Moreover, among children with normal ALT levels, principally reflecting perinatally required disease, response rates to interferon are much lower, on the order of 10% (Lancet 1987;2:877– 880, Q J Med 1991; 78:155–563). Based on these data, the use of interferon in children who are chronic carriers of HBV continues to remain controversial. Although some experts contend that earlier clearance of HBeAg by a few years is not worth the side effects and cost of interferon therapy (J Pediatr Gastroenterol Hepatol 2000;31:217–219), others have argued that the modestly increased rates of HBsAg seroconversion observed in patients treated with interferon justifies its use (Gut 2000;46:591– 593). Data regarding the use of lamivudine for the treatment of chronic HBV infection in children are limited. Anecdotal case reports (Transplantation 2001;72:333–336) and small, nonrandomized trials (Am J Gastroenterol 2000;95:2989 –2990, Antimicrob Agents Chemother 2000;44:590 –597) have suggested a modest clinical effect. In the present study, Jonas et al. conducted a randomized, placebo-controlled trial evaluating the efficacy and tolerability of lamivudine as a treatment for children chronically infected with hepatitis B. A total of 288 subjects between the ages of 2 and 17 years were randomly assigned in a 2:1 ratio to receive either oral lamivudine (3 mg/kg up to 100 mg maximum) or placebo once daily for a total of 52 weeks. Nearly half of the study patients had failed prior therapy with interferon. A virologic response, defined as loss of serum HBeAg and reduction of HBV DNA to undetectable levels, was significantly more likely in the lamivudinetreated patients (23%) vs. the control group (13%) and was even more pronounced after adjusting for greater response rates in patients with higher serum alanine aminotransferase (ALT) values and histologic activity index scores. In those lamivudine-treated subjects who exhibited a virologic response, 82% manifested sustained loss of HBeAg and HBV DNA at 6

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months. An additional 10% of patients originally assigned to receive lamivudine had a virologic response during the first 6 months of subsequent open-label treatment. At the end of the 52-week study period, mutations in the YMDD motif were detected in 19% of subjects receiving lamivudine. These patients had a markedly lower frequency of HBeAg loss, although mean serum ALT and HBV DNA levels remained substantially below baseline while on therapy. No significant adverse effects were encountered in either group. Comment. This well-designed study elegantly demonstrates that lamivudine is safe and modestly effective in stimulating HBeAg seroconversion in children chronically infected with HBV, findings which are highly analogous to results obtained in adults. Kudos are certainly in order as the performance of large clinical trials in pediatric populations are complicated by both ethical and practical difficulties in enrolling children, as well as by the lack of financial incentives for pharmaceutical companies to conduct such studies due to the relatively small market. It is notable that 80% of all drug products in the United States lack Food and Drug Administration (FDA)-approved labeling for use in neonates, infants, or children (Nat Med 2000;6:1069), greatly complicating the job of pediatricians who frequently must rely on their medical judgment to extrapolate appropriate dosing. The FDA Modernization Act of 1997, which provides economic inducements for pediatric trials, and the recently adopted Pediatric Rule requiring all new drug applications to include safety and efficacy data for children under the age of 17 years, are important steps in the right direction and are likely to dramatically increase information on the use of medicines in children. Unfortunately, while the original objectives of the trial were certainly achieved, the study by Jonas et al. raises many more questions than it answers regarding the management of children with chronic hepatitis B. Although lamivudine is certainly more convenient and better tolerated than interferon, and seems to be equally as effective, its use comes at the cost of developing YMDD-variant HBV. In contrast to interferon where patients receive treatment for a defined period of time, it has been suggested that those who develop YMDDvariant HBV while receiving lamivudine should be committed to long-term therapy to prevent the re-emergence of wild-type virus (Hepatology 2001;33:1527–1532, J Viral Hepat 2001;8:270 –275, Ann Intern Med 2000;132:723–731). However, the clinical implications of YMDD mutations and of the chronic administration of lamivudine to children are not entirely clear. Additionally, while the authors’ data indicate that children who fail a course of interferon are as likely to respond to lamivudine as those who are treatment naive, the converse is not necessarily true. Therefore, it could be reasonably argued that, in the absence of contraindications, interferon should be used as the first-line agent for chronic HBV, with lamivudine reserved for those patients who fail to respond, in essence giving them a second shot at seroconversion. The question of the use of combination therapy (interferon plus lamivudine) also remains unresolved (Gastroenterology 2001;120:1828 –1853), although initial results do not seem to be substantially better than those achieved with interferon or lamivudine monotherapy (Gut 2000;46:562–568, Hepatology 2001; 34:573–577, J Hepatol 2001;35:406 – 411, J Hepatol 2002;36:799 – 804, Pediatr Infect Dis J 2001;20:988 –992). Finally, it should be noted that the above discussion begs the issue of whether treatment of children with chronic hepatitis B is warranted at all given the efficacy of current treatment options. Despite statistical significance, rates of response to lamivudine remain relatively low, a mere 10 percentage points higher than the placebo

November 2002

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cohort. Hence, it would be necessary to treat 10 children with lamivudine for a year to achieve loss of HBeAg in a single individual that would have not done so spontaneously over the treatment interval. As has been observed in other studies, Jonas et al. found that higher serum ALT concentrations, more severe histologic activity, and lower HBV DNA levels are associated with a greater likelihood of virologic response to lamivudine. Limiting therapy to patients with these pretreatment characteristics would likely improve response rates, but would certainly exclude a large cohort of chronic HBV carriers with neonatally acquired infection. Although long-term follow-up studies of lamivudine-treated children are lacking, if findings are analogous to data for interferon then it may well be that therapy is accomplishing little more than accelerating the loss of HBeAg in those individuals already destined to seroconvert within a few years anyway. Before the advent of effective hepatitis B immunization regimens, it was estimated that the rate of HBV infection in children under the age of 10 years living in the United States was approximately 16,000 cases/year (Pediatrics 2001;108:1123–1128). The advent of universal vaccination strategies is likely to decrease this risk substantially. With a concerted worldwide effort, it is envisioned that hepatitis B ultimately will go the way of the polio virus, thereby making discussions regarding treatment moot. Hopefully, that day will come soon. However, in the meantime, studies such as this will help to guide and optimize therapy for those children unfortunate enough to become chronic carriers of HBV. STEPHEN D. ZUCKER, M.D.

Reply. Children represent a small proportion of cases of HBV infection in the United States, but childhood infection is very common in areas where HBV is endemic. Immigration and adoption of children from HBV-endemic areas continues. Although newborn vaccination and catch-up childhood immunization programs have been instituted, children in communities with the greatest risk have some of the lowest vaccination rates (Pediatrics 2000;106/6/e78). Chronically infected children are typically asymptomatic but act as

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reservoirs for HBV and eventual sources of parenteral, sexual, and/or perinatal transmission. Infections acquired in childhood are associated with significant morbidity later in life. For these reasons, it makes sense to consider treatment of HBV during childhood. It is true that the natural history of chronic HBV acquired in childhood includes a significant rate of spontaneous eAg to eAb seroconversion, especially in late childhood and young adulthood. However, the repeated flares of hepatitis that characterize many of these infections before this seroconversion may inflict significant hepatocellular injury ( J Pediatr Gastroenterol Nutr 1990;11:380 –384). The likelihood of cirrhosis, and perhaps of hepatocellular carcinoma as well, may be related to the length of time of viral replication. Therefore, shortening this period may have significant benefit. In addition, treatment during childhood with interferon alfa has been shown to be cost-effective ( J Pediatr Gastroenterol Nutr 1997;24:25–32), although a similar analysis for lamivudine has not been done. Lamivudine has been proven superior to placebo in hastening eAg seroconversion and halting viral replication. Factors such as baseline ALT and histopathologic scores influence the likelihood of these responses, underscoring the need for careful patient selection. For example, in our study the odds ratio of response to lamivudine for children whose ALT values were greater than twice normal was 3.4 (95% confidence interval, 175– 6.66). Lamivudine is well tolerated, but the optimal duration of therapy, considering the frequent development of viral resistance, has not been defined. Indefinite therapy, as is often instituted in adults, seems an impractical and potentially dangerous strategy in children. Treatment of all children with chronic HBV cannot be justified simply because lamivudine has a good safety profile and is tolerated well. In some children, however, virologic and biochemical improvement may have long-lasting implications. The need for development of rational and effective treatment strategies underscores the importance of large, well-designed therapeutic trials in this special population. MAUREEN M. JONAS, M.D.