esophageal stents in benign disease: A cause for concern. SurgLaparosc Endosc 1998;8:40–3.

17. Dumonceau JM, Cremer M, Lalmand B, et al. Esophagealfistula sealing: Choice of stent, practical management, andcost. Gastrointest Endosc 1999;49:70–8.

18. Adam A, Watkinson AF, Dussek J. Boerhaave syndrome: totreat or not to treat by means of insertion of a metallic stent.J Vasc Intervent Radiol 1995;6:741–6.

19. Yuasa N, Hattori T, Kobayashi Y, et al. Treatment of spon-taneous esophageal rupture with a covered self-expandingmetal stent. Gastrointest Endosc 1999;49:777–80.

20. Eubanks PJ, Hu E, Nguyen D, et al. Case of Boerhaave’ssyndrome successfully treated with a self-expanding metallicstent. Gastrointest Endosc 1999;49:780–3.

21. Goldin E, Fiorini A, Ratan Y, et al. A new biodegradable andself-expanding stent for benign esophageal strictures. Gastroi-ntest Endosc 1996;43:294 (abstract).

22. Fry SW, Fleischer DE. Management of a refractory benignesophageal stricture with a new biodegradable stent. Gastrin-test Endosc 1997;45:179–82.

23. Lee JG, Hsu R, Leung JW. Are self-expanding metal meshstents useful in the treatment of benign esophageal stenosesand fistulas? An experience of four cases. Am J Gastroenterol2000;95:1920–5.

24. Vaezi MF, Richter JE. Current therapies for achalasia: Com-parison and efficacy. J Clin Gastroenterol 1998;27:21–35.

25. Spiess AE, Kahrilas PJ. Treating achalasia: From whaleboneto laparoscope. JAMA 1998;280:638–42.

26. Orringer MB, Marshall B, Iannettoni MD. Transhiatalesophagectomy: Clinical experience and refinements. AnnSurg 1999;230:392–400.

27. Axelrad AM, Fleischer DE, Gomes M. Nitinol coil esophagealprosthesis: Advantages of removable self-expanding metallicstents. Gastrointest Endosc 1996;43:155–60.

28. Segalin A, Bonavina L, Siardi C, et al. Can the expandableesophageal metal Endocoil stent be safely removed? Endos-copy 1997;29:337–9.

Reprint requests and correspondence:Kevin M. McGrath,M.D., 216 Bell Building, Box 3902, Duke University MedicalCenter, Durham, NC 27710.

Received Mar. 9, 2000; accepted Apr. 28, 2000.

Nonsteroidal Anti-inflammatoryDrugs in Patients WithInflammatory Bowel DiseaseIt has been.100 yr since the first nonsteroidal anti-inflam-matory drug (NSAID), acetylsalicylic acid, was synthesizedby German chemists of the Bayer Corporation (1899) (1).However, salicylic acid, which is found in willow andpoplar tree bark, has been used since antiquity in the treat-ment of pain, arthritis, and fever. However, it was not untila report by Douthwaite and Lintott in 1938 (2) that providedthe first evidence of gastric injury secondary to aspirin. Bythe 1970s, large studies documented a clear associationbetween the use of NSAIDs and gastroduodenal mucosalulcerations. Also, over the past 25 yr, evidence has accu-mulated of the clear relationships between NSAIDs andmultiple types of mucosal injury to the distal small intestine

and colon, including bothde novolesions and exacerbationsof pre-existing disease (3).

There are a considerable number of published reports thatNSAIDs can exacerbate or lead to reactivation of preexis-tent inflammatory bowel disease (IBD), including the studyof Felderet al. (4) in this issue ofThe American Journal ofGastroenterology. In 1997, Evans reported on a prospectivecase-control study using a database to evaluate the relation-ship of NSAIDs and the risk of incident colitis secondary toIBD (5). Two hundred patients met the criteria of colitis dueto inflammatory bowel disease (IBD) (Crohn’s colitis, n5113; UG, n5 85; undetermined, n5 2). A total of 1178age- and sex-matched controls were compared to the IBDpatients. An odds ratio (OR) was calculated for current,recent, and past exposures to NSAIDs. An increased risk ofincident colitis due to IBD was associated with current andrecent exposure to NSAIDs (OR 2.96 [Cl: 95%, 1.32–6.64]and 2.51 [Cl: 95%, 1.13–5.55], respectively). These findingssupport the hypothesis that NSAIDs are implicated in colitisassociated with IBD.

The mechanism by which NSAIDs can cause the exac-erbation of IBD is not known. However, a probable con-tributing factor in leading to an exacerbation of colitis byNSAIDs is inhibition of colonic prostaglandin (PG) synthe-sis (6). The key enzyme in the synthesis of PG is cycloox-ygenase (COX). COX exists in two isoforms. COX-1 is aconstitutive enzyme and is involved in maintaining mucosalintegrity in the gastrointestinal (GI) tract. COX-1 is ex-pressed in many tissues including stomach, small intestine,colon, and others. On the other hand, COX-2 is an inducibleenzyme that is expressed primarily only at sites of inflam-mation. Proinflammatory cytokines such as tumor necrosisfactor induce COX-2 expression.

The ability of NSAIDs (including selective cyclooxygen-ase-2 inhibitors) to exacerbate pre-existing colonic ulcer-ation and inflammation in laboratory animals is well docu-mented. In a trinitrobenzene sulfuric acid model of colitis inthe rat, COX-2 expression was markedly increased afterinitiation of colitis (7). Exacerbations of colitis with colonicperforation resulted after therapy with selective COX-2 in-hibitors.

COX-1 messenger RNA (mRNA) has been identified inthe normal human colon by reverse-transcription polymer-ase chain reaction (8) and immunoblotting analysis (9).Singeret al. investigated the expression and distribution ofCOX-1 and COX-2 in the normal ileum, normal colon,ulcerative colitis, Crohn’s colitis, and Crohn’s ileitis (10). Inboth the small intestine and colon, COX-1 is expressed inthe lower crypt, but its expression is lost as the epithelialcells differentiate and migrate higher in the crypt. COX-1protein was expressed at equal levels in normal, Crohn’sdisease (CD), and ulcerative colitis (UC) colonic cells.COX-2 protein was not detected in normal epithelium butwas detected in CD and UC. COX-2 is not expressed inepithelial cells in areas removed from active inflammation(11).

1859AJG – August, 2000 Editorials

Therefore, the authors concluded that COX-1 expressionis unchanged in IBD (10). COX-2 was undetected in thenormal ileum and colon. However COX-2 was induced byinflammatory mediators in the more differentiated cells (i.e.,apical epithelial cells) of inflamed foci in IBD.

In 1997, Hendelet al. evaluated COX-2 expression in acontrolled, clinical study (UC, n5 22; CD, n5 11; inde-terminate IBD, n5 2) (12). Proctoscopy with biopsies forthe determination of mRNA of COX-1 and COX-2 wereobtained on all patients. Biopsies were obtained from themost endoscopically involved mucosal sites and comparedto patients with inactive IBD and healthy controls. Differ-ences in COX-1 mRNA were not detected. However thefraction of patients demonstrating COX-2 in mRNA assignificantly increased correlated with disease activity (p ,0.001). Hendelet al. concluded that COX-2 is involved inthe inflammatory response of chronic IBD.

The PGs produced through the epithelial cell COX-2 inIBD have a multifunctional role. PGs act over a shortdistance; therefore, the cellular distribution of COX-2 isimportant. Uribeet al. (1992) reported that PG E2 maymodulate cell proliferation in the small intestinal epitheliumof the rat (13). In addition to promoting epithelial prolifer-ation in the face of injury, PGs participate in the regulationof cytokine synthesis (10). Also the delay in wound healingwith COX-2 inhibition may relate to the loss of vasodilationand enhanced vascular permeability induced by PGs (14).

Expression of COX-2 in epithelial cells in IBD may act asa protective response, based on the following concepts.First, there is the expression of COX-2 in other types of GIinjury (15). Second, inhibition of GI wound healing canoccur by selective COX-2 inhibitors (10). Finally, therapeu-tic efficacy of exogenous PGs does occur in GI injury.Therefore, the inhibition of epithelial COX-2 in IBD pa-tients by NSAIDs could result in impairment of woundhealing.

The study by Bonneret al. (16) in this issue of theAmerican Journal of Gastroenterologycertainly reflects thatthere maybe subsets of IBD patients who can tolerateNSAID with less likelihood of an exacerbation of IBD.Because of the demographics of the clinic population inSouthern Florida, the study is based on “older age IBD.”Unfortunately, there can be confounding factors in studyingIBD in the elderly. Many diseases of the colon, includingIBD, may have atypical symptoms and findings in the el-derly. Second, other bowel diseases such as ischemia, di-verticulitis, and infectious colitis can mimic IBD in those ofretirement age. Therefore, recognition of specific intestinaldiseases can be obscure. In addition, altered immune re-sponses may occur in the elderly (17). However, the effectsof aging on changes in COX-2 expression are not known.Finally, wound healing can be a part of the natural progres-sion or continuum of the inflammatory state (15). Also, thesuccess of wound healing is based on factors in the elderlythat could alter this progression. Factors such as a patient’sage and the presence of concurrent illnesses that occur

frequently in the elderly (atherosclerosis, diabetes, etc.)could alter wound healing.

In summary, PG production through COX-2 may promoteepithelial proliferation and wound healing. Therefore,NSAIDs, including selective COX-2 inhibitors, which in-hibit PG synthesis, may impair the natural progression orcontinuum of the inflammatory state toward wound healing.

John O’Brien, M.D.Department of Gastroenterology

University of Indiana Medical CenterIndianapolis, Indiana

REFERENCES

1. Vance JR, Flower RJ, Rotting RM. History of aspirin and itsmechanism of action. Stroke 1990;21(suppl IV):12–23.

2. Douthwaite AH, Lintott JAM. Gastroscopic observation of theeffect of aspirin and certain other substances on the stomach.Lancet 1938;2:1222–5.

3. Cryer B. Nonsteroidal anti-inflammatory drugs and gastroin-testinal disease, and liver disease. In: Feldman M, Schar-schmidt B, Sleisenger M, eds. Sleisenger & Fordtran’s gas-trointestinal and liver disease: Pathophysiology/diagnosis/management. Philadelphia: WB Saunders, 1998:346–52.

4. Felder JB, Korelitz BI, Rejapakse R, et al. Effects of nonste-roidal antiinflammatory drugs on inflammatory bowel disease:A case-control study. Am J Gastroenterol 2000;95:1949–54.

5. Evans JM, McMahon AO, Murray FE, et al. Non-steroidalanti-inflammatory drugs are associated with emergency ad-mission to hospital for colitis due to inflammatory boweldisease. Gut 40:618–22.

6. Walace JL. Nonsteroidal anti-inflammatory drugs andgastroenteropathy: The second hundred years. Gastroenterol-ogy 1997;112:1000–16.

7. Reuter BK, Asfraha S, Buret A, et al. Exacerbation of inflam-mation associated isotonic injury in rat through inhibition ofcyclooxygenase-2. J Clin Invest 1996;98:2076–85.

8. O’Neil GP, Ford-Hutchinson AV. Expression of mRNA forcyclooxygenase-1 and cyclooxygenase-2 in human tissues.FEBS Lett 1993;30:156–60.

9. Kargman S, Charleston S, Cartwright M, et al. Characteriza-tion of prostaglandin G/H synthesis 1 and 2 in rat, dog,monkey and human gastrointestinal tracts. Gastroenterology1996;111:445–54.

10. Singer II, Kowka DW, Schloeman S, et al. Cyclooxogenase 2is induced in colonic epithelial cells in inflammatory boweldisease. Gastroenterology 1958;115:297–306.

11. Houchen CW, Stenseon WM. 1 Cyclooxygenase expression inintestinal epithelial cells. Current Opin Gastroenterol 15:97–9.

12. Hendel J, Nielsen OH. Expression of cyclooxygenase-2mRNA in active inflammatory bowel disease. Am J Gastro-enterol 1997;92:1170–3.

13. Uribe A, Alam M, Midveet T. E2 prostaglandin modulates cellproliferation in the small intestine epithelium of the rat. Di-gestion 1992;52:157–64.

14. Williams TJ. Prostaglandin E2, prostaglandin T2, and vascularchanges of inflammation. Br J Pharmacol 1979;65:517–23.

15. Stenson WE. Cyclooxygenase-2 and wound healing in thestomach. Gastroenterology 1997;112:645.

16. Bonner GF, Walczak M, Kitchen L, et al. Tolerance of non-steroidal antiinflammatory drugs in patients with inflammatorybowel disease. Am J Gastroenterol 2000;95:1946–8.

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17. Schneider EL. Infectious disease in the elderly. Ann InternMed 1988;108:616.

Reprint requests and correspondence:John O’Brien, M.D., Uni-versity of Indiana Medical Center, Department of Gastroenterol-ogy, Medical Research Building, 550 North University Boulevard,Suite 2300, Indianapolis, IN 46202.

Future Directions in the MedicalTreatment of Primary SclerosingCholangitis: The Need forCombination Drug TherapyIn this issue of theJournal, van Hoogstratenet al. presentthe results of an 8-wk randomized, double-blind pilot studycomparing the effects of budesonide (BUD) in combinationwith ursodeoxycholic acid (UDCA)versusprednisone incombination with UDCA in patients with primary sclerosingcholangitis (PSC) (1). A relatively small sample of 18 pa-tients currently receiving UDCA (mean dose 12 mg/kg/day)were recruited and randomized to 10 mg/day of prednisone(n 5 6), 3 mg/day of BUD (n5 6), or 9 mg/day of BUD(n 5 6). The results of this study suggest that the short-termuse of prednisone and BUD do not lead to any significantimprovement in clinical or biochemical parameters in pa-tients currently receiving UDCA. Only minor short-termeffects on symptoms and liver biochemistries were observedwith prednisone but not with BUD. From these results,Hoogstratenet al. conclude that the apparent risk–benefitratio does not support the long-term evaluation of suchagents.

PSC is a poorly understood chronic cholestatic liver dis-ease, with no adequate medical therapy shown to relievesymptoms successfully or to delay the progression to liverfailure (2). Although a variety of therapeutic agents withdifferent mechanisms of action have been used, none havebeen of convincing benefit. Controlled trials to evaluate thecupruretic effect of D-Penicillamine by La Russoet al., andthe antifibrogenic effect of colchicine by Olssonet al., donot demonstrate any clinically significant effect on diseaseprogression or survival (3, 4). The most widely used andstudied medication in PSC has been UDCA. Although mosttrials have shown some improvement in liver biochemistrieswith UDCA at a dose of 10–15 mg/kg/day, a recent ran-domized trial including 105 patients did not demonstrateany clinical benefit in altering disease progression or time totransplantation (5–7). This is in contrast to PBC, for whichlong-term data indicate that UCDA increases survival anddelays the time to transplantation (8–10).

A close association with inflammatory bowel disease andspecific HLA haplotypes, as well as the presence of numer-ous immunological abnormalities in PSC, point to immune-mediated mechanisms in the pathogenesis of PSC (11). Avariety of immunosuppressant medications have been ex-

amined including methotrexate, cyclosporine, and tacroli-mus (FK506) (12–14). Controlled studies with methotrexateand cyclosporine, however, have not demonstrated any fa-vorable effect on prognosis or outcome. In a single reportedtrial of tacrolimus involving 10 patients, there was a signif-icant improvement in liver biochemistries after 1 yr (14).Corticosteroids including prednisone have also been exam-ined, usually in short-term studies. However, long-term sideeffects including osteoporosis are of particular concern inpatients with PSC who are already at risk for significantosteopenic bone disease (15). At this time, there is noconvincing evidence that corticosteroids alone are of clini-cal benefit in PSC.

Most recently, budesonide, a second-generation cortico-steroid with a reported high first-pass metabolism and min-imal systemic availability, has been the focus of clinicaltrials in PSC (1, 16, 17). In recent controlled trials withPBC, BUD in combination with UCDA seemed to conferpotential benefits (18). Unfortunately preliminary experi-ence, including the pilot study by van Hoogstratenet al., donot point to any obvious clinical benefits in PSC (1, 17, 18).Furthermore, these studies suggest that the systemic avail-ability of BUD is clinically important at the studied dose of9 mg/day in that osteoporosis may be aggravated. Newantiresorptive drugs such as the bisphosphonates may havea promising role in patients receiving corticosteroid therapywho also have or develop osteoporosis. In a small 11-wktrial evaluating the efficacy of etidronate in patients withPBC receiving corticosteroid therapy, cyclical etidronateseemed to prevent bone loss (19). Further studies withcorticosteroids and bisphosphonates in PSC patients areclearly needed.

Combination therapy is a relatively new avenue of clin-ical research in the treatment of chronic cholestatic diseasessuch as PBC and PSC. Drugs in monotherapy are oftenlimited by efficacy and dose-related toxicity. However,combination therapy, in which different drugs with differentmechanisms of action are used either together or in a se-quential manner, may hold the potential for improved effi-cacy through additive or synergistic effects. In addition,individual drug toxicities may potentially be minimized bythe need for lower effective doses. Although there have beenseveral trials of multidrug regimens in PBC, only a fewmultidrug approaches for the treatment of PSC have beenexplored in isolated case reports and preliminary trials,including colchicine in combination with prednisone, andmethotrexate in combination with UDCA (20–25). Combi-nation approaches using multiple immunomodulatoryagents in PSC have been reported only in a single casereport in which a combination of cyclosporin and pred-nisolone resulted in marked improvements by cholangio-graphic criteria (25). The study by van Hoogstratenet al. inthis issue of theJournal therefore represents an importantnew direction for clinical research in PSC.

Will there ever be any effective medical treatments inPSC? Future success in the medical treatment of PSC will

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