Do Non-steroidal Anti-inflammatory Drugs Cause Exacerbations of Inflammatory Bowel Disease?

Transcription

1 Dig Dis Sci (2010) 55: DOI /s REVIEW Do Non-steroidal Anti-inflammatory Drugs Cause Exacerbations of Inflammatory Bowel Disease? Linda A. Feagins Byron L. Cryer Received: 11 September 2009 / Accepted: 26 October 2009 / Published online: 19 November 2009 Ó Springer Science+Business Media, LLC 2009 Abstract The safety of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with inflammatory bowel disease (IBD) remains unclear. This report discusses potential mechanisms whereby NSAIDs might exacerbate IBD and reviews the available clinical data on the role of NSAIDs in causing exacerbations of ulcerative colitis (UC) and Crohn s disease (CD). Keywords Non-steroidal anti-inflammatory drugs Inflammatory bowel disease Crohn s disease Ulcerative colitis Abbreviations CD Crohn s disease COX Cyclooxygenase DSS Dextran sodium sulfate GI Gastrointestinal IBD Inflammatory bowel disease NF-kB Nuclear factor kappa B NSAID Non-steroidal anti-inflammatory drug PDAI Pouch disease activity index PGE2 Prostaglandin E2 Disclosures: LA Feagins has no potential conflicts relevant to the manuscript. BL Cryer is a consultant for PLx Pharma, Sucampo Pharmaceuticals, Pozen Inc., Pfizer Inc., Horizon Therapeutics, Astra- Zeneca, NiCox Inc., McNeil, Inc., and Ritter Pharmaceuticals, and has grant/research support from PLx Pharma, Sucampo Pharmaceuticals, Pozen Inc., and Pfizer Inc. L. A. Feagins (&) B. L. Cryer Divisions of Gastroenterology (111B1) and Hepatology, VA North Texas Health Care System and the University of Texas Southwestern Medical Center at Dallas, 4500 South Lancaster Road, Dallas, TX 75216, USA LindaA.Feagins@va.gov QOL UC Clinical Scenario Quality of life Ulcerative colitis A 54-year-old man is seen for follow-up of ileal Crohn s disease (CD) that was first diagnosed 20 years ago. He has been doing well for the past 8 years on azathioprine alone, and he has no bowel complaints today. He does complain of chronic joint pains, especially in his hands, that his rheumatologist thinks are caused by osteoarthritis. He has taken acetaminophen with no relief. His rheumatologist would like to prescribe a non-steroidal anti-inflammatory drug (NSAID) for the arthritis, but he is concerned that this medication might cause the Crohn s disease to flare. How should this patient be counseled? Introduction Inflammatory bowel disease (IBD) is characterized by chronic, relapsing intestinal inflammation of unknown etiology. IBD also is associated with extra-intestinal inflammatory conditions, like arthritis, that may respond to treatment with NSAIDs. For patients with IBD, paradoxically, it has been proposed that the use of those antiinflammatory medications can cause the bowel inflammation to flare. Data to support this contention are limited, however, and a causal link between the use of NSAIDs and flares of IBD has not been established unequivocally. This report discusses potential mechanisms whereby NSAIDs might exacerbate IBD and reviews the available clinical

2 Dig Dis Sci (2010) 55: data on the role of NSAIDs in causing exacerbations of ulcerative colitis (UC) and Crohn s disease. To collect relevant articles, a PubMed search was performed up to June 2009 using the term ulcerative colitis or Crohn s disease or inflammatory bowel disease in combination with non-steroidal anti-inflammatory drugs, NSAIDs, COX-2 inhibitors, cyclooxygenase, or NF-kB. Relevant English language articles were reviewed, as were their reference lists to identify further articles. Pathophysiology of Gastrointestinal Injury Due to NSAIDs Upper Gastrointestinal Tract NSAIDs can clearly injure the mucosa of the upper gastrointestinal (GI) tract, resulting in gastric and duodenal ulcerations that can be complicated by bleeding, stricture formation, and perforation. There are two known mechanisms whereby NSAIDs can cause these deleterious effects in the upper GI tract [1, 2]. First, NSAIDs can cause a toxic, topical effect in the stomach due to local accumulation within gastric cells. In acidic gastric juice, the weakly acidic NSAIDs are in an un-ionized form, in which they can freely penetrate gastric cells. In the neutral ph environment within the cell, H? ions dissociate and the negatively charged NSAID molecule cannot cross the cell membrane. In this manner, potentially injurious NSAIDs rapidly become concentrated within the mucosal cells. This can cause an increase in cellular permeability and local damage [3], manifested endoscopically as erosions, hyperemia, and submucosal hemorrhage. The second, and more important, mechanism by which NSAIDs cause GI injury is through their systemic effects on prostaglandin synthesis, which is regulated by the enzyme cyclooxygenase (COX). NSAIDs inhibit COX activity, leading to depletion of the prostaglandins that normally protect the mucosa by enhancing mucosal defense mechanisms. These defense mechanisms include maintaining mucosal blood flow, regulating the secretion of mucus and bicarbonate, inhibiting acid secretion, and regulating gastric motility [2]. COX, which derives from the metabolism of arachidonic acid, has two key forms important for the regulation of prostaglandin synthesis, COX-1 and COX-2. COX-1 is constitutively expressed in abundance throughout the GI tract, catalyzing the production of prostaglandins important for the maintenance of GI integrity, such as prostaglandins E2 (PGE2) and I2 (PGI2). Conversely, there is little expression of COX-2 in normal GI tissues at baseline, but this enzyme is rapidly inducible and appears to be the principle COX involved in inflammation. Additionally, little COX-2 is produced in the stomach. Until recently, it was believed that most of the GI toxicity attributable to NSAIDs was due to their inhibition of the protective effects of COX-1. It was hoped that the adverse GI side-effects of NSAIDs could be avoided by instead using COX-2-selective NSAIDs like celecoxib and rofecoxib. Unfortunately, these drugs are not entirely devoid of GI toxicity, and enthusiasm for their use has been dampened substantially by the realization that the COX-2- selective NSAIDs are associated with cardiovascular risks [4, 5]. Furthermore, it has been appreciated recently that COX-2 also contributes substantially to mucosal defense and repair, particularly in response to injury, and seems to work in parallel with COX-1 [6]. NSAIDs have also been demonstrated to have antiinflammatory actions that are not related to their effects on prostaglandin synthesis. Most notably, some NSAIDs, like ibuprofen and flurbiprofen, have been shown to inhibit the activation of nuclear factor kappa B (NF-kB), which plays a central role in mediating the production of inflammatory cytokines and enzymes, and as a regulator of immune cell differentiation and apoptosis (programmed cell death) [7]. However, the contribution of NF-kB inhibition to the GI toxicity of NSAIDs is not clear. Small Intestine and Colon The toxicity of NSAIDs in the small bowel and colon is thought to be related primarily to the direct mucosal effects of these drugs. The increasing use of enteric-coated or sustained-release NSAIDs in an attempt to decrease gastroduodenal injury may inadvertently have shifted some damage by these agents from the upper GI tract to the small bowel and colon [8]. In support of this concept, NSAIDs that are quickly absorbed in the stomach or duodenum and do not undergo enterohepatic circulation have been noted to cause less small bowel injury [1, 9]. Exposure of the small bowel mucosa to NSAIDs is thought to lead to the loss of intracellular integrity and increased permeability because the NSAIDs damage surface membrane phospholipids and cause an uncoupling of oxidative phosphorylation [10, 11]. The recirculation of NSAIDs in the enterohepatic circulation leads to repeated injuries of this type. This damage to the small intestinal barrier then allows further injury and subsequent inflammation caused by intraluminal factors, such as bile, bacteria, and food. Potential Mechanisms for NSAID-Induced Exacerbations of IBD COX inhibition. Studies evaluating the possible mechanisms underlying NSAID-induced flares of IBD are relatively few in number, but some potential mechanisms have

3 228 Dig Dis Sci (2010) 55: been elucidated. One possible mechanism that emerges from the above discussion is that NSAIDs cause the inhibition of COX, which leads to decreased prostaglandin synthesis which, in turn, results in an inability to maintain the mucosal defenses needed to prevent inflammation in the bowel. This mechanism is supported by animal studies using the dextran sodium sulfate (DSS)-induced model of colitis, which have shown that treatment with the NSAID indomethacin causes an exacerbation of the colitis [12, 13]. Tanaka also found that indomethacin suppressed the expression of mucin proteins (muc2 and muc3) and reduced intestinal mucosal cell growth, effects that could be reversed by the administration of PGE2 [12]. Okayama found that selective COX inhibitors (including SC-560, which inhibits COX-1 selectively, and celecoxib, a COX-2-selective NSAID) did not worsen DSS-induced colitis, whereas another group also studying DSS-induced colitis (but in rats instead of mice) found that celecoxib and SC-560 did worsen colitis. This group also investigated the time course of NSAID-induced exacerbation of colitis and found that COX-1 was important for mucosal protection in the early stage of DSS-induced colitis, whereas COX-2 was the predominant isoform effecting mucosal protection in the later stages of inflammation [13]. In a human study involving 100 IBD patients who were in remission, groups of 20 patients each were treated with one of five medications: (1) acetaminophen, (2) naproxen (a non-selective NSAID), (3) nabumetone (another nonselective NSAID), (4) nimesulide (a COX-2-selective agent), or (5) low-dose aspirin (primarily a COX-1 inhibitor at low dose) [14]. Within 4 weeks of these treatments, relapse of IBD symptoms occurred in four patients each in the naproxen and nabumetone groups, but in only one patient each in the acetaminophen and nimesulide groups, and in no patient in the aspirin group. These data represent IBD relapse rates of 20% for patients treated with nonselective NSAIDs compared to only 0 5% for patients treated with COX-selective NSAIDs or acetaminophen. However, this study is limited in that it was not randomized or blinded, and it is not clear how patients were assigned to each of the treatment groups. Leukotriene shunting. In addition to COX, another important metabolic pathway of the metabolism of arachidonic acid is lipoxygenase. Metabolism via this pathway results in the production of leukotrienes, lipoxin, and hydroxyl fatty acids [15]. These leukotrienes are proinflammatory and elevated levels of leukotrienes have been found in the tissues of IBD patients and were correlated with disease activity [16, 17]. Speculation can be made that treatment with NSAIDs, particularly those that inhibit both COX-1 and COX-2, may shunt the metabolism of arachidonic acid via the lipoxygenase pathway, leading to worsened inflammatory bowel disease activity. Interestingly, however, treatments for IBD aimed at inhibition of the lipoxygenase pathway have, so far, been unsuccessful in trials [18]. Inhibition of NF-kB activity. Another potential mechanism for NSAIDs to cause flares of IBD is through effects on pathways independent of COX inhibition. As mentioned above, NSAIDs have been shown to inhibit NF-kB activity [19] and NF-kB is known to play a key role in the immune response in patients with IBD [20]. Activated NF-kB moves to the nucleus, where it acts as a transcription factor for a number of genes, including COX-2, pro-inflammatory mediators like interleukin-23 (IL23) and interleukin-17 (IL17), and mucin proteins [19, 21, 22]. Therefore, NSA- IDs that interfere with the NF-kB pathway might cause a decrease in the intestinal production of COX-2 and mucin and alterations in pro-inflammatory signaling. It is conceivable that such alterations might exacerbate IBD, but further studies are needed to confirm the role of NSAIDs in causing IBD flares and to elucidate the underlying mechanisms. NSAID Use in IBD: Do Clinical Studies Provide the Evidence for Causality? A possible pathogenetic link between NSAID use and IBD exacerbations was first appreciated in the 1980s, when a number of case reports and small series documented the clinical and endoscopic relapse of IBD in patients who had used NSAIDs [23]. Since then, IBD flares have been reported after the use of non-selective NSAIDs such as aspirin, ibuprofen, indomethacin, and naproxen, as well as after the use of COX-2-selective agents like celecoxib and rofecoxib. Although the case reports and observational studies describing the association between NSAIDs and IBD flares cannot be considered as definitive, practice guidelines prepared by the American College of Gastroenterology have deemed the use of NSAIDs to be a potential exacerbating factor for IBD [24, 25]. A number of retrospective case control studies and cohort studies have been conducted to clarify the role of NSAIDs in causing flares of IBD (see Table 1). In a cohort study published in 1983, Rampton found that a group of patients who were seen for flares of ulcerative colitis reported a significantly higher use of paracetamol or NSAIDs (aspirin, phenylbutazone, and mefenamic acid) than a group of patients seen with ulcerative colitis in remission (76 vs. 39%, P = 0.01) [26]. If paracetamol use is excluded from that analysis, then the difference is 28 vs. 17% (odds ratio 1.85) for NSAID use. A retrospective case control study using a large pharmacy database found a significant association between emergency room visits

4 Dig Dis Sci (2010) 55: Table 1 Clinical studies investigating a role for non-steroidal anti-inflammatory drugs (NSAIDs) in flares of inflammatory bowel disease (IBD) Reference Year Author Diagnosis No. of patients Study design Study drug Follow-up Outcomes Controlled prospective studies [35] 2006 Sandborn [34] 2004 Biancone [33] 2003 Reinisch UC 222 Randomized, double-blinded, placebo Celecoxib 200 mg bid 2 weeks 3 vs. 4% flares (P = 0.719) UC and CD UC and CD 45 Open-label Rofecoxib 12.5 mg per day 3 days 3 months 20% flare sx 32 Open-label Rofecoxib mg/day 20 days No flares but 9% drug discontinuation for GI sx [29] 2007 Shen Pouchitis 11 Prospective cohort NSAID withdrawal 4 weeks Reduction of PDAI -3.6 ±-3 (P \ 0.02) and improved QOL scores (P \ 0.05) [14] 2006 Takeuchi UC and CD 109 Controlled but not blinded or randomized* Naproxen (32), diclofenac (29), indomethacin(22), acetaminophen (26) (Two arms) 100 Controlled but not blinded or randomized* Acetaminophen, naproxen, nabumetone, nimesulide, aspirin Retrospective/cross-sectional/cohort studies [36] 2006 Meyer UC, CD, or IC [32] 2002 Mahadevan UC, CD, pouchitis 60 Chart review of NSAID use in patients with active vs. inactive disease 4 weeks 17 28% flare with non-selective NSAIDs vs. no flares with tylenol 4 weeks 20% relapse in non-selective NSAIDs vs. 0-5% in COX-2, COX-1, or non- NSAIDs Daily NSAID use or more 9/22 (41%) active and 10/38 (26%) inactive with NSAID use 27 Chart review Celecoxib or rofecoxib 2/27 (7.4%) with worsened IBD [37] 2004 Matuk UC, CD 33 Questionnaire of previous use Celecoxib or rofecoxib 13/33 (39%) with disease exacerbation [27] 1997 Evans Colitis (CD or UC) 200 Pharmacy record review of ER admissions Any NSAID Odds ratio 1.77 (current use) and 1.93 (recent use) for NSAID use and ER admission [28] 2000 Felder UC, CD 60 Questionnaire at time of admission for flare Any NSAID within 1 month prior to flare [31] 2004 Bonner [26] 1983 Rampton UC, CD 629 Calculation of disease activity and questionnaire about NSAID use at clinic visits UC 83 Questionnaire of previous use within the last 4 weeks (remission vs. relapse) [38] 1990 Riley UC 92 Longitudinal cohort, followed pts with inactive disease, q12wk questionnaires, compared those who flared to those who stayed in remission 31% with correlation b/w NSAID use and onset of flare Any NSAIDs No relation of NSAID use to significant flares All analgesics 6/21 relapsers and 11/62 remission used NSAIDs Any NSAID 48 weeks Too few patients taking NSAIDs to make good comparison * Not clear from the methodology of the paper whether this study is randomized or blinded

5 230 Dig Dis Sci (2010) 55: for exacerbations of colitis and the use of NSAIDs, with an odds ratio of 1.77 and 1.93 for current and recent exposure to NSAIDs, respectively [27]. Another small study of patients hospitalized for an acute flare of colitis found that 31% of those patients reported that they had used NSAIDs within the preceding month, whereas only 2% of a control group comprised of patients with IBS reported such NSAID usage [28]. Another cohort study of 17 patients who had symptomatic pouchitis and who were using NSAIDs found that the discontinuation of the NSAIDs resulted in an overall significant improvement in pouchitis activity and quality of life (QOL) scores [29]. In contrast to the aforementioned reports, other clinical studies have not detected any clear adverse effects of NSAIDs for patients with IBD. A retrospective study reported in 2000 comprising outpatients with IBD (both Crohn s disease and ulcerative colitis) compared the frequency of NSAID usage in patients whose disease flared with that of patients whose IBD remained quiescent [30]. The investigators found no significant differences in the frequency of NSAID usage between those two groups. The same investigators then conducted a prospective study, again in outpatients with IBD, collecting data on NSAID usage and bowel disease activity during serial clinic visits over a 5-year period for 426 patients with Crohn s disease and 203 patients with ulcerative colitis. Again, the investigators found no significant association between NSAID usage and flares of IBD [31]. Another study looked retrospectively at a group of 27 patients with IBD who were treated with either rofecoxib or celebrex for a median of 9 months and found that only two patients had worsening of their Crohn s disease during that time [32]. A potential shortcoming of studies exploring the relationship between NSAID usage and IBD flares is that an incipient flare may result in symptoms that cause the patient to seek relief with NSAIDs. In this situation, investigators may find a significant association between NSAID usage and flares, but the NSAIDs may have no pathogenetic role in those flares. Recently, a number of prospective studies have been performed in which IBD patients have been purposely exposed to NSAIDs, providing more compelling data on whether NSAIDs contribute to IBD flares. A study by Takeuchi, discussed previously, treated patients who had quiescent IBD without arthritic complaints with either acetaminophen or one of three non-selective NSAIDs (naproxen, diclofenac, or indomethacin) for 4 weeks [14]. There were no flares in the patients given acetaminophen, whereas 17 28% of the patients given NSAIDs experienced an IBD flare. The investigators explored whether the adverse effects of NSAIDs could be attributed to the inhibition of COX-1, COX-2, or both by treating patients with nimesulide (a COX-2-selective NSAID), naproxen (a non-selective NSAID), nabumetone (a non-selective NSAID), low-dose aspirin (primarily COX-1-selective at low doses), or acetaminophen. Interestingly, there were significantly more IBD flares in the groups treated with the non-selective NSAIDs (naproxen and nabumetone) than in the other groups. Of note, however, it is not clear if this study was randomized or blinded. Two open-label studies have been performed on the use of rofecoxib in IBD patients who had musculoskeletal complaints with varying results [33, 34]. One study found no flares of IBD during treatment with rofecoxib, but 9% of the patients had to stop the medication due to GI complaints [33]. The other study found that 20% of patients had to stop rofecoxib due to GI symptoms, which the investigators attributed to IBD relapse [34]. The only published randomized, controlled, double-blinded trial is by Sandborn, who randomized 222 patients with quiescent ulcerative colitis (not on steroids) to receive two weeks of either a COX-2-selective inhibitor (celecoxib) or placebo [35]. The investigators found no significant difference in the frequency of disease exacerbation between the celecoxib and placebo groups (3 vs. 4%, respectively), supporting the notion that COX-2 inhibitors do not cause IBD flares, at least not in the short term. No randomized study of non-selective NSAIDs has been performed, so the safety of these medications remains unclear. Summary and Recommendations The safety of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with inflammatory bowel disease (IBD) remains unclear. Nevertheless, physicians must frequently advise IBD patients with chronic musculoskeletal pains, such as the one presented earlier in this report. NSAIDs can clearly have toxic effects in the gastrointestinal (GI) tract and mechanisms proposed to underlie their ability to exacerbate IBD seem plausible. However, the clinical data to support the notion that NSAIDs lead to IBD flares are inconclusive. Treatment with cyclooxygenase-2 (COX-2) inhibitors, at least for the short term, seems to cause no increased risk of flare of quiescent ulcerative colitis. However, the clinician must also consider the cardiovascular risks associated with the use of COX-2-selective NSAIDs. No randomized, blinded trials with COX-2 have been done in Crohn s disease patients. The current data on the non-selective NSAIDs are limited and some studies describe contradictory results. A randomized controlled trial of non-selective NSAIDs compared to acetaminophen in IBD patients with chronic musculoskeletal pains is needed. Unfortunately, for now, the question of whether non-selective NSAIDs cause IBD flares remains unanswered. Presently, clinical experience would suggest that, avoiding NSAID use, particularly in difficult-to-

6 Dig Dis Sci (2010) 55: control IBD patients, would be prudent, while a cautious trial of NSAIDs in well-controlled patients may be tolerated. In the case presented here, our patient was given a trial of etodolac with no flare of his Crohn s disease and much improved control of his osteoarthritis pain. Acknowledgments We are grateful to Dr. Stuart J. Spechler for his thoughtful review of the manuscript and helpful suggestions. References 1. Pusztaszeri MP, Genta RM, Cryer BL. Drug-induced injury in the gastrointestinal tract: clinical and pathologic considerations. Nat Clin Pract Gastroenterol Hepatol. 2007;4: Laine L, Takeuchi K, Tarnawski A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology. 2008;135: Cryer BL, Spechler SJ. Peptic ulcer disease in Sleisenger & Fordtran s gastrointestinal and liver disease pathophysiology/ diagnosis/management. 8th ed. 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