Prevalence and Mechanism of Nonsteroidal Anti-Inflammatory Drug–Induced Clinical Relapse in Patients With Inflammatory Bowel Disease

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<ul><li><p>PDB</p><p>KR*BI</p><p>BntaaflmCNv2vtmdpntCaoanTigrttst</p><p>Cat((e</p><p>CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4:196202revalence and Mechanism of Nonsteroidal Anti-InflammatoryrugInduced Clinical Relapse in Patients With Inflammatoryowel Disease</p><p>EN TAKEUCHI,* SIMON SMALE,* PURUSHOTHAMAN PREMCHAND,* LAURENCE MAIDEN,*OY SHERWOOD, BJARNI THJODLEIFSSON, EINAR BJORNSSON, and INGVAR BJARNASON*Department of Internal Medicine, Guys, Kings, St Thomas Medical School, London, United Kingdom; Department of Clinicaliochemistry, Kings College Hospital, London, United Kingdom; Department of Gastroenterology, University Hospital Iceland, Reykjavik,celand; and Department of Gastroenterology, Sahlgrenska University Hospital, Gothenburg, Sweden</p><p>tpnpiaCatimia</p><p>tfntcisliumtrtmecs</p><p>s</p><p>ackground &amp; Aims: It has been variably suggested thatonselective NSAIDs and cyclooxygenase (COX)-2 selec-ive inhibitors aggravate or ameliorate clinical diseasectivity in patients with inflammatory bowel disease. Wessessed the effect of these drugs in patients with in-ammatory bowel disease (n 209) and the possibleechanisms. Methods: First, patients with quiescentrohns disease and ulcerative colitis received the non-SAID analgesic acetaminophen (n 26) and the con-entional NSAIDs naproxen (n 32), diclofenac (n 9), and indomethacin (n 22) for 4 weeks. The Har-ey-Bradshaw index was used to define relapse. Second,o assess the mechanism of relapse, intestinal inflam-ation was quantitated (fecal calprotectin) before anduring treatment (20 patients/group) with acetamino-hen, naproxen (topical effect, COX-1 and -2 inhibitor),abumetone (COX-1 and -2 inhibitor), nimesulide (selec-ive COX-2 inhibitor), and low-dose aspirin (selectiveOX-1 inhibition). Results: Nonselective NSAIDs weressociated with a 17%28% relapse rate within 9 daysf ingestion. No patient had an early relapse on acet-minophen, nimesulide, or aspirin, whereas those onaproxen and nabumetone (20%) experienced relapse.hese clinical relapses were associated with escalatingntestinal inflammatory activity. Conclusions: NSAID in-estion is associated with frequent and early clinicalelapse of quiescent inflammatory bowel disease, andhe mechanism appears to be due to dual inhibition ofhe COX enzymes. Selective COX-2 inhibition with nime-ulide and COX-1 inhibition with low-dose aspirin appearo be well-tolerated in the short-term.</p><p>onventional NSAIDs are the most prescribed of theanti-rheumatic drugs, which attests to their efficacy</p><p>s anti-inflammatory analgesics. These therapeutic ac-ions are largely due to inhibition of cyclooxygenaseCOX)-2. The side effects of NSAIDs on the stomachNSAID-gastropathy)1 and the small bowel (NSAID-</p><p>nteropathy)2 are, however, of considerable concern, con-ributing significantly to the morbidity and mortality ofatients receiving these drugs long-term.3 The mecha-isms underlying this damage are complex and incom-letely understood. In experimental animals the damages initiated by various combinations of the 3 biochemicalctions common to all conventional NSAIDs,2,4 ie,OX-1 inhibition, COX-2 inhibition, and the topicalction. The biochemistry of this topical action is thoughto involve an NSAIDsurface membrane phospholipidnteraction5 and/or an effect on mitochondrial energyetabolism,2 both of which are consequent to the phys-</p><p>cochemical properties of conventional NSAIDs, namelycidity and their high lipid solubility (lipophilicity).</p><p>Conventional NSAIDs are occasionally implicated inhe development of de novo colitis,2,6 but they are morerequently involved in aggravating pre-existing intesti-al diseases.2 This is most obviously illustrated in pa-ients with the inflammatory bowel disease ulcerativeolitis and Crohns disease, who frequently require anti-nflammatory analgesics because of peripheral arthritis,acroiliitis, ankylosing spondylitis, and osteoporosis-re-ated fractures.7 Although early studies suggested thatntestinal inflammation and symptoms in patients withlcerative colitis improved with NSAID treatment,8,9</p><p>ost subsequent studies, albeit not all,10,11 suggestedhat NSAIDs might be one of the causes of clinicalelapse of inflammatory bowel disease.1217 In either casehere are substantial uncertainties as to the possibleechanisms (inhibition of COX-1 or COX-2, the topical</p><p>ffect, or a combination of these). Theoretically it isonceivable that selective COX-2 inhibition exerts aimilar anti-inflammatory effect in the inflamed intestine</p><p>Abbreviations used in this paper: COX, cyclooxygenase; NSAID, non-teroidal anti-inflammatory drug. 2006 by the American Gastroenterological Association Institute</p><p>1542-3565/06/$32.00</p><p>PII: 10.1053/S1542-3565(05)00980-8</p></li><li><p>aaiCoirrtrfpnitmdewcd</p><p>cgiflwt</p><p>bpptib1rctdaPcswwNrctm</p><p>cdgssmdnsms</p><p>(wpcgpmw(p</p><p>cawt</p><p>February 2006 NSAID-INDUCED RELAPSE IN PATIENTS WITH IBD 197s it does in inflamed joints. The data in human beingsre inconclusive. There are reports of exacerbation ofnflammatory bowel disease with the use of selectiveOX-2 inhibitors celecoxib and rofecoxib,1820 whereasthers consider them safe.21 A significant problem fornterpretation of these studies is that many are caseeports, and some are retrospective in which the temporalelationship between the disease activity and drug inges-ion is not always clear. Furthermore, patients in clinicalemission with substantial inflammation, as reflected byecal calprotectin concentrations (a neutrophil selectiverotein) that are in 5-fold excess of the upper limit oformal,22 are at particular risk of a spontaneous clin-cal relapse. Finally, the clinical disease activity indiceshat are used to define the clinical relapse can be made toimic relapse of disease with NSAIDs, because these</p><p>rugs frequently cause abdominal pain, diarrhea, nausea,tc23 in rheumatic patients as well as healthy volunteersithout a corresponding inflammatory response that</p><p>haracterizes the clinical relapse of inflammatory bowelisease.24,25</p><p>The aims of this study were to assess the prevalence oflinical relapse of inflammatory bowel disease wheniven conventional NSAIDs, to assess whether the clin-cal relapse is associated with escalating intestinal in-ammation, and to assess the possible mechanisms, ie,hether it is due to inhibition of COX-1 or COX-2, the</p><p>opical effect, or a combination of these effects.</p><p>Subjects and MethodsPatients with ulcerative colitis and Crohns disease</p><p>etween the ages of 2070 years were invited to participate,rovided that they were in clinical remission. These wereatients attending gastroenterology outpatient clinics wherehey are followed up every 412 months. The diagnoses ofnflammatory bowel disease were biopsy and/or radiologicallyased in all and had been made between 223 years (median,1 years) before this study. The diagnosis was verified byeview of case notes and interview according to acceptedriteria.26 The principal inclusion criterion for this study washat patients were in full clinical remission defined by clinicalisease activity score questionnaire, and that they had not hadclinical relapse during the last 6 weeks requiring treatment.atients on NSAIDs or aspirin, those with serious psychiatric,ardiovascular, respiratory, renal, hepatic, and central nervousystem disease, malignancy, and women at risk of pregnancyere specifically excluded as were those misusing alcohol orith a history of substance misuse. A history of significantSAID intolerance (hypersensitivity reactions, asthma, acute</p><p>hinitis, urticaria, and angioneurotic edema) was an exclusionriterion. However, patients who had experienced adverse gas-rointestinal side effects (dyspepsia or flare-up of their inflam-</p><p>atory bowel disease) of NSAIDs in the past were not ex-luded, but it is possible that some of these would haveeclined participation in this study. Patients who had under-one extensive surgery (colectomy, colostomy, ileostomy,mall bowel resection of more that 40 cm, bypass or diversionurgery) were excluded. Also excluded were patients receivingore than 10 mg prednisolone/day, those requiring elemental</p><p>iets or nutritional support, and those who had received tumorecrosis factor antibodies (or other biologicals) or undergoneurgery during the preceding 6 months. No change in treat-ent for inflammatory bowel disease was made during the</p><p>tudy.Altogether 209 patients with inflammatory bowel disease</p><p>ulcerative colitis/Crohns disease) underwent study. Thereere 2 aspects to these studies. The first part involved 109atients with inflammatory bowel disease to assess whetheronventional NSAIDs caused clinical relapse of disease wheniven during a period of 4 weeks. Thirty-two of these werelaced on naproxen (500 mg twice a day), 29 on diclofenac (75g twice a day), and 22 on indomethacin (75 mg twice a day),hereas 26 received the non-NSAID analgesic acetaminophen</p><p>1 g 3 times a day), and these served as a control group forossible spontaneous clinical relapse of disease.The second part assessed the possible mechanism of the</p><p>linical relapse by administering drugs that have differentialctions on the COX enzymes and the topical effect. Patientsere assigned to 1 of 5 groups (20 patients/group) and received</p><p>he following:</p><p>1. Acetaminophen (1 g 3 times a day) as a non-NSAIDcontrol (acetaminophen does not inhibit COX-1 orCOX-227 or have the topical effect28)</p><p>2. Naproxen (500 mg twice a day), a conventional NSAID(naproxen inhibits COX-1 and COX-227 and exerts thetopical effect28)</p><p>3. Nabumetone (1 g twice a day), a non-acidic pro-NSAID, which undergoes hepatic biotransformation tothe active component, 6-methoxy-2-naphthylaceticacid, which is not excreted in bile (nabumetone does nothave a topical effect,28 whereas 6-methoxy-2-naphthyl-acetic acid inhibits both COX-1 and COX-2,27 but theintestine is not exposed to its topical action)</p><p>4. Nimesulide (100 mg twice a day), a preferential orselective COX-2 inhibitor29 (nimesulide inhibitsCOX-2 without affecting COX-1 significantly at thesedoses,27,29 and it does not have a topical effect30)</p><p>5. Aspirin (75 mg once a day). At this low dose, aspirinappears to be a relatively selective COX-1 inhibitor.Although aspirin is acidic and therefore exerts a topicaleffect, most of the dose is absorbed from the stomachand duodenum (aspirin is not excreted in bile), and asignificant topical effect on the rest of the gastrointes-tinal tract is unlikely31 and has not been evident withhigher (2.4 g) doses in human beings.32 It is, however,more difficult to assess whether aspirin has an effect onCOX-2 at these doses. Ex vivo studies indicate that it</p><p>does not inhibit COX-2,33,34 it is not associated with</p></li><li><p>mr1s(wds</p><p>T</p><p>Ka</p><p>cifwdbcHi2</p><p>ngcwtwtr</p><p>opnptasdpl(</p><p>httaoTtqcgom</p><p>le4</p><p>gtcD</p><p>T</p><p>MAU</p><p>C</p><p>T</p><p>198 TAKEUCHI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 2any significant anti-inflammatory action (a COX-2dependent action),35 and judging from its COX-1 se-lectivity in vitro,27 it seems to be a relatively selectiveCOX-1 inhibitor at these doses.</p><p>All drug treatments in both parts of the study were for 1onth unless the activity score met the criteria for clinical</p><p>elapse, in which case drug treatment was discontinued. The00 patients in the second part of the study also underwenttudies that allowed quantitation of intestinal inflammationfecal calprotectin) before and after 1 and 4 weeks of treatmentith the drugs. When a clinical relapse occurred or if theyiscontinued the study, these patients collected the next stoolample for calprotectin measurement.</p><p>The demographic details of the patients are shown inable 1.These studies were approved by the ethical committees of</p><p>ings College Hospital and Sahlgrenska University Hospital,nd all patients gave informed consent.</p><p>Clinical Disease Activity</p><p>Clinical remission was defined as a Harvey-Bradshawlinical disease activity index36 of 4 or less during the preced-ng week. Although the Harvey-Bradshaw index was designedor use in patients with Crohns disease, we used it for patientsith both Crohns disease and ulcerative colitis as previouslyone.22,37 All patients completed diary cards during the weekefore drug treatment and then a daily diary if there was ahange in clinical symptoms. A clinical relapse was defined asarvey-Bradshaw score of equal to or greater than 5 and an</p><p>ncrease of 4 or more from the pretreatment baseline values onconsecutive days while receiving the drugs.Some of the side effects of NSAIDs, such as diarrhea and</p><p>onspecific crampy abdominal pain,23 cannot be easily distin-uished on clinical grounds from the diarrhea associated withlinical disease activity of inflammatory bowel disease. Patientsere warned about the possible occurrence of upper gastroin-</p><p>estinal dyspepsia, nausea, and nonspecific abdominal pain andere instructed not to include these in the questionnaire unless</p><p>his had been a prominent feature of their previous clinical</p><p>able 1. Demographic and Clinical Details</p><p>Acetaminophen Naproxen Diclofe</p><p>ale/female 12/14 14/18 19/1ge (y) median (range) 37 (2462) 40 (2070) 33 (20lcerative colitisTotal 5 4 5Left-sided 5 5 7Proctitis 6 3 5</p><p>rohns diseaseSmall bowel 4 11 7Colonic 6 9 5</p><p>reatmentMesalamine 17 19 16Azathioprine 7 6 3Corticosteroids 2 1 0elapse. tIntestinal Inflammation</p><p>Intestinal inflammation was assessed by measurementf calprotectin in feces. Calprotectin is a neutrophil selectiverotein (also present in small quantities in other polymorpho-uclear white cells), which resists bacterial degradation.38 Itsresence in feces relates quantitatively to the neutrophil flux tohe gastrointestinal tract, ie, it is proportional to the degree ofcute inflammation.24,39 Patients in the second part of thetudy provided a stool sample within 3 days of commencingrug treatment and on days 7 and 28 during treatment. In caseatients fulfilled the criteria for a clinical relapse, they col-ected the next stool sample for calprotectin measurementsthis was in all cases within 24 hours of the clinical relapse).</p><p>Stool samples were delivered to the laboratory within 48ours and were frozen at 20C on arrival. Samples werehawed at room temperature, and the calprotectin concentra-ion was determined by an enzyme-linked immunosorbentssay after an extraction procedure as previously described24,38</p><p>r with the use of a commercial kit (Calprest; Eurospital,rieste, Italy).40 The 2 methods are essentially comparable in</p><p>heir performance, sensitivity, and specificity,40 but they giveuantitatively different data. The commercial kit providesalprotectin values and upper normal limits that are 5 timesreater than the older assay. All the results obtained with theld method during these studies were therefore presented afterultiplying the values by a factor of 5.The normal range of fecal calprotectin concentration (upper</p><p>imit of normal is 52 g/g stool), with the commercial kit, wasstablished by the laboratory in 88 healthy volunteers (42 men,6 women; median age, 47 years; range, 2070 years).</p><p>Statistics</p><p>The statistical differences between the treatmentroups (clinical relapses) were tested with 2-tailed Fisher exactest with Yates correction. Sequential changes in calprotectinoncentrations we...</p></li></ul>