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elective Use of Selective Nonsteroidalnti-Inflammatory Drugs in Inflammatoryowel Disease

onsteroidal anti-inflammatory drugs (NSAIDs) arethe medications most commonly used as a first

esort for the aches and pains of daily life and thosessociated with numerous diseases. More than 70 millionSAID prescriptions are written annually in the Unitedtates. In addition, 30 billion over-the-counter NSAIDablets are sold each year.1 Although generally safe, gas-rointestinal (GI) toxicities, including NSAID-related ul-er disease and associated bleeding, remain a significanthallenge. Overall mortality in the United States causedy NSAIDs, largely as a result of GI complications, haseen estimated conservatively at 16,500 deaths annual-

y1—a mortality rate greater than that from gastric can-er in 2004.2

A less common but significant concern is the potentialafety of NSAID use specifically in patients with inflam-atory bowel disease (IBD). IBD patients have numer-

us reasons to seek relief for both IBD-related and non–BD-related pains (eg, arthralgias and arthritides are theost frequent extraintestinal manifestations of IBD, af-

ecting an estimated 10%–35% of patients). Unfortu-ately, early reports suggested that NSAIDs may exacer-ate IBD,3,4 and physicians have viewed ulcerative colitisUC) and Crohn’s disease as relative or absolute contra-ndications for prescribing this class of medication.

However, the magnitude of the risk of NSAIDs fornciting disease activity in IBD patients has not beenssessed adequately. There have been relatively fewtudies and most, if not all, suffer from methodologiceaknesses. Evans et al5 suggested a role for NSAIDs inrecipitating disease flares after studying individuals ad-itted for IBD exacerbations through the emergency

oom. These patients had an increased likelihood ofurrent or recent (within 180 days) exposure to NSAIDs.onner et al6 failed to find an association with low-doseSAID use and disease activity but suggested that high-ose NSAID use may increase activity of colonic Crohn’sisease. A case-control study by Felder et al7 confirmed a

ikely effect of NSAIDs in worsening disease activity inoth Crohn’s disease and UC. Despite the disparate find-

ngs and frequent limitations in study design, the pre-onderance of evidence supports an effect of nonselec-ive NSAIDs on disease exacerbations. However, theagnitude of this effect is not well defined, and it is not

lear if some patient subgroups or individuals are atarticularly high risk.The target enzyme of these medications is cyclooxy-

enase (also known as prostaglandin synthase), which

xists as 2 isoenzymes: cyclooxygenase-1 (COX-1) and p

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OX-2, and converts arachidonic acid into prostaglan-ins. COX-1 is a constitutive enzyme expressed in virtu-lly all tissues and is involved in a variety of homeostaticellular functions controlling mucosal blood flow, mu-us secretion, acid regulation central to gastrointestinalytoprotection, renal blood flow, and platelet aggrega-ion. In contrast, constitutive expression of COX-2 is lowr nonexistent in most cell types. Instead, expression is

nduced by a variety of inflammatory cytokines and lipo-olysaccharides. The expression of COX-2 in the intes-ine correlates with inflammatory activity in IBD.8 Al-hough COX-2 generally is inducible, it is notable that its expressed constitutively in some organs and con-ersely COX-1 may function in a minor role as part of thecute inflammatory response.

All NSAIDs used before 1998 inhibited both COX-1nd COX-2. Selective COX-2 inhibitors (named coxibs)ere developed with the hope that they would provide

he analgesic benefit of NSAIDs without gastrointestinaloxicity. The first of these to become generally available,elecoxib (Celebrex; Pfizer Inc, New York, NY) waspproved by the Food and Drug Administration in 1998,nd rofecoxib (Vioxx; Merck & Co, Inc, Whitehousetation, NJ) was approved the following year. Studies ofoxib use in IBD patients to date have been limited andave yielded contradictory results. Although data nowoint to an increase in cardiovascular morbidity andortality among the general population taking coxibs,

ome studies have suggested that these compoundsight be safer and better tolerated by IBD patients thanonselective NSAIDs. Mahadevan et al9 suggested in aetrospective case series that fewer than 10% of IBDatients had disease flare associated with a coxib. How-ver, Matuk et al10 found in another retrospective studyhat nearly 40% of patients, mostly with Crohn’s disease,xperienced an exacerbation of their disease within 6eeks on a coxib, and a higher percentage flared on

elecoxib (7 of 10, 70%) compared with rofecoxib (6 of1, 29%). Open-labeled prospective studies of rofe-oxib11,12 suggested a low risk for inducing flares (13%)ith up to 3 months of use, but a relatively higher rate

9%–20%) of drug discontinuation owing to GI side ef-ects than seen in the general population. The increasedisease activity described in these previous reports re-olved in most patients soon after discontinuation of thessociated drug and without additional medication.

Two articles in this issue of Clinical Gastroenterologynd Hepatology help address questions about the risksf coxib use in IBD patients. In the first article, Sandbornt al13 performed a large, prospective, double-blind, pla-ebo-controlled trial in which 222 patients with UC inemission were randomized to celecoxib at 200 mg or

lacebo twice daily for 2 weeks. The results showed that

NICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4:157–159

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158 EDITORIALS CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 2

hort-term (2 weeks) use of celecoxib is not associatedith induction of flares during that period in UC patientsho are in remission and not taking corticosteroids.hus, 3% of patients receiving the medication flareduring the 2 weeks compared with 4% receiving pla-ebo. The clinical scoring index was confirmed by flex-ble sigmoidoscopies before and at the conclusion of the-week period. Although 3% in both groups discontin-ed the medication because of other adverse GI events,hese were problems distinct from UC symptoms. In theecond study, Takeuchi et al14 used a more complexesign aimed to address a broader set of questions. In therst part of their study, 4 different analgesics were giveno individuals (n � 109) with quiescent Crohn’s diseaser UC for 4 weeks: acetaminophen (n � 26), naproxenn � 32), diclofenac (n � 29), or indomethacin (n � 22).he second part of their study compared nonselectiveSAIDs with a selective inhibitor (nemusilide, not avail-

ble in the United States) and low-dose aspirin (a rela-ively selective COX-1 inhibitor). Disease activity wasssessed using the Harvey–Bradshaw index and clinicalelapse was confirmed by an increase in fecal calprotec-in. None of the patients on acetaminophen, aspirin, orhe selective COX-2 inhibitor experienced an increase inBD activity compared with a 17%–28% incidence ofares in the nonselective NSAID groups.From their results, Takeuchi et al14 inferred that theechanism inducing flares requires concurrent inhibi-

ion of both COX-1 and COX-2. Studies in animal modelsupport this conclusion. Interleukin-10 null mice de-elop more severe colitis with more rapid onset wheniven nonselective NSAIDs.15 However, treatment with aOX-1– or COX-2–specific inhibitor does not induceolitis, implying that inhibition of both COX-1 andOX-2 is required to affect the development of colitis in

his model. The relevant prostaglandins responsible forhe cascade of events involved in a flare remain uncer-ain. Although COX-2 is induced as part of the inflamma-ory response, some prostaglandins generated are anti-nflammatory (eg, prostaglandin E2 increases interleukin-0,16 a counterinflammatory cytokine, while decreasingther proinflammatory cytokines such as tumor necrosisactor).17 Indeed, a study using an acetic acid–inducedodel of colitis suggested that selective inhibition ofOX-2 can even have a potential therapeutic role18 in

reating active intestinal inflammation in some settings.How can clinicians use this new information concern-

ng NSAIDs and coxibs? Studies have suggested that upo 50% of IBD patients use NSAIDs, at least intermittent-y.6 How should they be instructed? The use of COX-2–elective NSAIDs in IBD patients does appear less wor-isome (when focusing specifically on the relationship toI disease) than the nonselective agents. The coxibs mayave less GI toxicity across the board: for ulcer disease,leeding, and in IBD. The study by Takeuchi et al14

nvestigated the issue of safety of a variety of NSAID

ompounds in the IBD population and suggested thatonselective NSAIDs are likely to cause a flare within 4eeks of administration in 17.2% of patients, a suffi-

iently high risk as to recommend their avoidance inost patients. Aspirin, at least at a low dose, appears to

e safer and may be a possible short-term alternative.The information we have from Sandborn et al13 con-

rms the short-term safety for the use of celecoxib inatients with UC in remission who are not on steroids.s the investigators emphasized, there were a number of

mportant limitations of their study. Patients on pred-isone were excluded because glucocorticoids suppressrachidonic acid metabolism, decreasing prostaglandineneration from both COX isoenzymes. The risk of aOX-2–selective inhibitor given together with pred-isone conceivably could be similar to that of a nonse-

ective inhibitor. The action of COX-2 inhibition in activeisease may be very different and the present data onafety in patients in remission cannot be extrapolated toatients with active disease. Finally, it will be necessaryo factor the growing evidence of an increased risk forardiovascular events into the complex calculus to as-ess the overall risk-benefit ratio for IBD patients who areandidates for celecoxib (currently the only COX-2–elective compound available in the United States).

In summary, these studies are important as small stepsorward in the care of IBD patients. They indicate thatonselective inhibitors carry a significant risk for exac-rbating IBD whereas celicoxib is safe for 2 weeks foratients in remission. Low-dose aspirin use remains in aray zone of uncertain but probable safety. However,hese data should not open the floodgates for the use ofelecoxib in IBD patients. Unfortunately, the studies didot evaluate a longer period of medication use. Givenhe current controversies with COX-2 inhibitors, longer-erm studies or even short-term studies in other IBDubgroups seem unlikely at this point. Still, with theurrent information, celecoxib is safe in certain IBDatients for short-term use: an important, even if small,dvance.

JOSHUA R. KORZENIK, MDDANIEL K. PODOLSKY, MD

Gastrointestinal Unit, Department of MedicineCenter for the Study of Inflammatory Bowel Disease

Massachusetts General Hospital andHarvard Medical School

Boston, Massachusetts

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2. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CACancer J Clin 2004;54:8–29.

3. Kaufmann HJ, Taubin HL. Nonsteroidal anti-inflammatory drugs

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February 2006 SELECTIVE NSAIDS IN IBD 159

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4. Rampton DS, Sladen GE. Relapse of ulcerative proctocolitis dur-ing treatment with non-steroidal anti-inflammatory drugs. Post-grad Med J 1981;57:297–299.

5. Evans JM, McMahon AD, Murray FE, et al. Non-steroidal anti-inflammatory drugs are associated with emergency admission tohospital for colitis due to inflammatory bowel disease. Gut 1997;40:619–622.

6. Bonner GF, Fakhri A, Vennamaneni SR. A long-term cohort studyof nonsteroidal anti-inflammatory drug use and disease activity inoutpatients with inflammatory bowel disease. Inflamm Bowel Dis2004;10:751–757.

7. Felder JB, Korelitz BI, Rajapakse R, et al. Effects of nonsteroidalantiinflammatory drugs on inflammatory bowel disease: a case-control study. Am J Gastroenterol 2000;95:1949–1954.

8. Hendel J, Nielsen OH. Expression of cyclooxygenase-2 mRNA inactive inflammatory bowel disease. Am J Gastroenterol 1997;92:1170–1173.

9. Mahadevan U, Loftus EV Jr, Tremaine WJ, et al. Safety of selec-tive cyclooxygenase-2 inhibitors in inflammatory bowel disease.Am J Gastroenterol 2002;97:910–914.

0. Matuk R, Crawford J, Abreu MT, et al. The spectrum of gastroin-testinal toxicity and effect on disease activity of selective cyclo-oxygenase-2 inhibitors in patients with inflammatory bowel dis-ease. Inflamm Bowel Dis 2004;10:352–356.

1. Biancone L, Tosti C, Geremia A, et al. Rofecoxib and early relapseof inflammatory bowel disease: an open-label trial. Aliment Phar-macol Ther 2004;19:755–764.

2. Reinisch W, Miehsler W, Dejaco C, et al. An open-label trial of theselective cyclo-oxygenase-2 inhibitor, rofecoxib, in inflammatorybowel disease-associated peripheral arthritis and arthralgia. Ali-

ment Pharmacol Ther 2003;17:1371–1380.

3. Sandborn WJ, Stenson WF, Brynskov J, et al. A selective cyclo-oxygenase-2 inhibitor, celecoxib, is safe in patients with ulcer-ative colitis in remission. Clin Gastroenterol Hepatol 2006;4:203–211.

4. Takeuchi K, Smale S, Premshand P, et al. Prevalance and mech-anism of NSAID-induced clinical relapse in patients with inflam-matory bowel disease. Clin Gastroenterol Hepatol 2006;4:196–202.

5. Berg DJ, Zhang J, Weinstock JV. Rapid development of colitis inNSAID-treated IL-10-deficient mice. Gastroenterology 2002;123:1527–1542.

6. Harizi H, Juzan M, Pitard V, et al. Cyclooxygenase-2-issued pros-taglandin e(2) enhances the production of endogenous IL-10,which down-regulates dendritic cell functions. J Immunol 2002;168:2255–2263.

7. Betz M, Fox BS. Prostaglandin E2 inhibits production of Th1lymphokines but not of Th2 lymphokines. J Immunol 1991;146:108–113.

8. El-Medany A, Mahgoub A, Mustafa A, et al. The effects of selec-tive cyclooxygenase-2 inhibitors, celecoxib and rofecoxib, on ex-perimental colitis induced by acetic acid in rats. Eur J Pharmacol2005;507:291–299.

Dr Korzenik has received consulting and lecture fees from Proctor &amble, Shire Pharmaceuticals, Isis Pharmaceuticals, Cytokine Phar-asciences, Berlex, and Centocor and research support from Danisco.US patent entitled “Stimulating Neutrophil Function to Treat Inflam-atory Bowel Disease (6500418)” was issued December 31, 2002. Drorzenik is one of the inventors. The patent is owned by Washingtonniversity and licensed by Berlex Laboratories.

PII: 10.1053/S1542-3565(05)01095-5