Gary R. Lichtenstein, MD, FACG

Transcription

1 Symposium B: Clinical Challenges in IBD A Case-based Approach refractory ibd Gary R. Lichtenstein, MD, FACG Key Take Home Points Establish the correct extent, type of IBD (UC versus CD) and establish disease activity. Identify complications of disease (abscesses, strictures, fistulas) and treat these appropriately. Exclude the presence of enteric infections (especially C. diff, enteric infections and CMV). Optimize medications being used while evaluating for drug intolerances. Avoid NSAIDs, cigarettes (particularly in CD) and consider surgery when appropriate. Learning Objectives Upon completion of this session, the participant should be able to: Define factors responsible for patients having refractory IBD. Develop an approach the treatment of a patient with refractory IBD. Introduction One of the most difficult aspects of caring for patients with inflammatory bowel disease (IBD) is the high frequency of incomplete or absent response to medical therapy. Although many patients may be truly refractory to medical therapy, a lack of response may be a consequence of several possibilities including incorrect diagnosis, progression of disease extent, intestinal complication (abscess, stricture, mesenteric venous thrombosis, dysplasia, concurrent celiac sprue), superinfection, under-dosing of therapy, development of antidrug antibodies, or medication intolerance. I will outline a practical general approach to refractory IBD for caregivers in clinical practice. Establish The Correct Diagnosis and Extent of Disease Initially, it is important to correctly identify the specific IBD diagnosis (ulcerative colitis versus Crohn s disease) and determine the extent and severity of disease. Crohn s disease (CD) and ulcerative colitis (UC) are often treated in a different manner hence establishing the correct diagnosis is of paramount importance. The diagnosis of the specific subtype of IBD is established with clinical history and radiographic, endoscopic, and histologic consistent with a particular IBD subtype. IBD patients who were previously in remission who experience an exacerbation or who are refractory to medical therapy mandate evaluation of disease location. In patients with ulcerative colitis, those patients with distal of left sided colitis may have disease progression more proximally. A Danish study illustrates that 41% of patients with proctosigmoiditis have disease advance more proximally over a 10 year period. When patients have disease exacerbations over a prolonged time period, it is important to do colonoscopy with mucosal biopsies. If the disease is severe to fulminant then consideration of a flexible sigmoidoscopy should occur. The colonoscopy helps evaluate for the presence of malignancy, dysplasia, viral infections (e.g. CMV), evaluate for the presence of strictures, evaluate if the disease is either CD or UC, confirm the extent of disease, evaluate the disease activity. In patients who are suspected of having UC, the evaluation of the small bowel is important at some time in their disease course (particularly if disease becomes refractory or surgery is being contemplated). This evaluation may take place in the form of a CT enterography, enteroclysis or video capsule endoscopy. In patients with established disease, it is similarly important to reimage after flares to help identify disease related complications such as fistulas or intestinal stricture. Cross sectional imaging (CT scan of the abdomen and pelvis) should be considered in patients with refractory disease. Disease Complications Disease related complications in patients with IBD may contribute to poor clinical response in refractory patients and should be diagnosed. A frequently observed scenario is when a patient has fibrostenotic CD that is inappropriately treated as inflammatory CD. Individuals identified as having refractory CD patients should undergo a small bowel barium study or CT enterography to exclude the presence of structuring disease; however, small intestinal narrowing can be caused by inflammation nor fibrosis and may often produce a similar appearance. Laboratory and radiographic features may help to distinguish inflammatory disease from fibrotic disease. Those factors that are suggestive of inflammatory changes include elevation in erythrocyte sedimentation rate or C-reactive protein level, mucosal hyper-enhancement on the CT enterography. Factors most suggestive of fibrotic disease included the presence of stricture associated with prestenotic dilatation, or lack of 104 Symposium B: Clinical Challenges in IBD A Case-based Approach

2 clinical response to corticosteroids. If there is a fibrostenotic stricture then medical therapy will not benefit patients; rather surgical resection or stricturoplasty is indicated. Patients with refractory CD or those with febrile episodes or those with significant leukocytosis should have assessment for intra-abdominal abscesses. The presence of characteristic symptoms or findings may not be present in all patients. Abscesses may be identified by CT of the abdomen and pelvis or MRI of the abdomen and pelvis (for patients who possess iodine contrast allergy). Frequently, MRI scans of the pelvis are more capable of identifying pelvic abscesses than are CT scans. Once identified, intra-abdominal abscesses are classically treated by surgery or percutaneous drainage. Evaluation for the presence toxic colonic dilation should be performed with either plain abdominal radiography or CT radiography. The presence of toxic megacolon may occur in patients with colitis of differing disease extents. Patients with toxic megacolon typically manifest with a fulminant course. Avoidance of antimotility agents should be the standard in this scenario. Enteric Infections The presence of enteric infections can simulate active IBD both clinically and endoscopically or may contribute to flares of established disease. In all patients with refractory IBD, it is of utmost importance to exclude such infections. Assessment for enteric pathogens, Clostridium difficile should be routinely performed at times of disease flares in patients with IBD. Routine pathogens commonly encountered include routine Salmonella, Shigella, Campylobacter, E. coli O157:H7, and Aeromonas. Approximately 50-80% of the world s population is seropositive for CMV. Initial CMV infection in the immune competent host is typically mild and goes undetected clinically. This is then followed by a chronic latent state, during which the virus remains present within host cells, but viral proliferation is prevented by host cell-mediated immunity. When immune containment fails, reactivation with viral proliferation and severe systemic illness may ensue. Systemic CMV disease is characterized by fever, pancytopenia, and inflammatory changes in multiple organs including the liver and lungs, and in the retina. Colitis is a frequent manifestation of this acute systemic illness. Patients are rendered susceptible to systemic CMV disease by treatment with immunosuppressive medications or by illnesses that reduce cellular immunity, such as human immunodeficiency virus (HIV) infection. Acute systemic illness caused by CMV is particularly common following initial exposure in an immune compromised individual. Table 1: Sensitivity and Specificity of Different Clostridium Difficile Testing Methods Method Sensitivity (%) Specificity (%) Enzyme Immunoassays Cell culture neutralization Glutamate dehydrogenase* paired with toxin testing (2-step algorithm) Anaerobic toxigenic culture > Nucleic acid amplification CMV disease in IBD patients occurs in the presence of colonic mucosal inflammation and ongoing immunosuppressant therapy. A positive test for CMV IgG indicates that a person was infected with CMV at some time during their life but the IgG test cannot determine when a person was infected. If antibody tests of paired acute- and convalescent-phase serum samples show a four-fold rise in IgG antibody and CMV IgM antibody is present or CMV virus is cultured from a urine or throat specimen, an active CMV infection is present. In general, it is the immune suppression that has leads to reactivation of CMV in a patient leading to systemic infection. Cessation of immunosuppression is the first step while treating with antiviral therapy. Antiviral therapy is very effective in this scenario. Clostridium difficile is another pathogen that has been associated with exacerbations of IBD. The prevalence of infection with this organism among IBD patients with flares may be as high as 28%. It is important to recognize that the presence of C. difficile infection can be detected in IBD patients even in the absence of recent antibiotic exposure. Several different tests have been reported in the literature for testing for C. diff and are summarized in Table 1. The role of C. difficile infection in contributing to exacerbation of IBD is somewhat controversial. Several reports have suggested that C. difficile infections may actually be fairly uncommon and of limited importance whereas other reports have found that stool studies are useful to exclude active infection in patients with IBD disease flares. In a recent series, the prevalence of C. difficile infection was 19%, and most patients improved with antibiotic therapy. Lastly, detailed exposure, travel and social l histories should be taken to determine the need for testing for parasitic infections in patients with IBD. Symposium B: Clinical Challenges in IBD A Case-based Approach 105

3 Use of Optimal Medication Doses Ulcerative Colitis Inadequate dosing of medication can lead to active disease. In UC patients with mild-to-moderate disease activity, oral aminosalicylates have been shown to be effective for induction of remission. Oral therapy with the aminosalicylates (sulfasalazine, olsalazine, mesalamine, or balsalazide) is benefi cial in achieving and maintaining remission. Effective doses of sulfasalazine range between 4 and 6 g a day in four divided doses; for mesalamine 2 and 4.8 g per day in three divided doses; for balsalazide 6.75 g per day in three divided doses; and for olsalazine g per day in two divided doses, although efficacy of olsalazine in active UC is not conclusively established, perhaps in part because of a confounding dose-related diarrhea. Another mesalamine formulated with a multimatrix formulation allows comparable efficacy with once daily dosing in doses of g per day. These drugs generally exert their effect within 2-4 weeks. In general, if patients still have active symptoms on maximum doses of oral mesalamine then addition of topical therapy in the form of a nightly mesalamine enema should be considered in UC patients. A recent study demonstrated that a combination of oral mesalamine 2.4 and 4 g per day mesalamine enema was more effective in achieving clinical improvement, as well as an earlier response, than either agent alone. This concept has also been shown in patients with pancolitis; the addition of topical therapy is superior to oral therapy with mesalamine alone. The use of azathioprine in doses up to mg / kg per day have shown its effectiveness in patients who do not respond to, or cannot be weaned from steroids. Their primary benefit is in the steroid sparing effect, rather than as an agent to be used as monotherapy to induce remission. Methotrexate has not been proven to be effective in UC when administered in a weekly dose of 12.5 mg orally per day. There has not been any evaluation yet completed on higher dose administration or administration by a parenteral route in controlled trials. Methotrexate is currently being evaluated as a once weekly subcutaneously administered medication in UC (using 25 mg sq once weekly). In two double-blind, placebo-controlled trials, ACT 1 and ACT 2, infliximab was given every 8 weeks after a loading dose regimen of 5 or 10 mg / kg at weeks 0, 2, and 6. This treatment was found to be effective to maintain response and remission at week 30 (53% and 32%, respectively), and week 54 (45% and 42%, respectively) in those patients with an initial response or remission at week 8. There was no benefit to initial treatment with the higher dose. Although not studied in a controlled manner in these trials, some patients with an initial response to 5 mg / kg in whom the benefit is attenuated after multiple doses may benefit from dose escalation, or shortening dosing intervals, or both. In these studies, similar response and remission rates were noted whether patients had been steroid refractory or steroid naïve; but the success rate in maintaining a steroid-free remission at week 54 was only 21%. In addition, these studies did not prospectively address whether concomitant thiopurine therapy would influence clinical success rates. If a patient develops severe disease despite optimal doses of oral steroids (40-60 mg daily of prednisone), oral aminosalicylates (4-6 g sulfasalazine, 4.8 g mesalamine or 6.75 g balsalazide), and topical medications then immediate hospitalization should be orchestrated. The primary therapy for those patients requiring hospitalization at this point is an intravenous steroid in a daily dose equivalent to 300 mg hydrocortisone or 60 mg methylprednisolone. There is no benefit to treatment with higher daily dose of steroids; and it is established that higher doses expose patients to a higher potential rate of side effects. Failure to show significant improvement within 3-5 days is an indication for either colectomy or treatment with intravenous infliximab or cyclosporine in the patient with severe colitis. A recent trial by Laharie et al. evaluated patients who failed (Lichtiger disease activity score >10 points) at least 5 days of treatment with i.v. methylprednisolone at the daily dose of at least 0.8 mg/kg. Patients were randomly assigned to therapy with either cyclosporine A (2mg/kg/day) for one week followed by switching to oral formulation during 98 days or three infusions of infliximab (5mg/kg) administered at weeks 0, 2 and 6. The primary endpoint was treatment failure that was defined as absence of clinical response at day 7 or absence of remission at day 98 or relapse between day 7 and day 98 or severe adverse event necessitating discontinuation of treatment or colectomy or death. There were similar rates of treatment failures in cyclosporine A and infliximab groups (60% vs. 54%, p=0.49). There were 10 severe adverse events reported in 9 patients receiving cyclosporine A and 16 events in patients receiving infliximab but no fatalities were observed in either of groups. Another study, the SUCCESS trial evaluated in a randomized double blind controlled trial in biologic naïve patients with moderate to severe UC who failed corticosteroid therapy and either were naïve to azathioprine or discontinued azathioprine at least 3 months prior to the trial onset. The patients received either azathioprine (2.5mg/kg) and placebo (arm 1), infliximab (5mg/kg) and placebo (arm 2) or infliximab (5mg/ kg) and azathioprine (2.5mg/kg) (arm 3). Those in arm 1 who did not respond (reduction in Mayo score less than 1 point) at week 8 were permitted to be treated with infliximab 5 mg/kg at weeks 8, 10 and 14. The primary endpoint was 106 Symposium B: Clinical Challenges in IBD A Case-based Approach

4 corticosteroid- free remission at week 16 defined as total Mayo score 2 points. Combination therapy with infliximab and azathioprine resulted in achieving significantly (p<0.05) greater corticosteroid-free remission rates at week 16 (40%) when compared to monotherapy with azathioprine (24%) or infliximab (22%). The use of antibiotics as primary therapy for the treatment of patients with ulcerative colitis has shown no therapeutic benefit. Specific trials that have been done include the use of oral vankomycin, intravenous metronidazole, or ciprofloxacin, when added to intravenous steroids. However, protocols outlining treatment regimens for severe colitis generally include broad-spectrum antibiotics for patients with signs of toxicity, or with worsening symptoms despite maximal medical therapy. Crohn s Disease As per data outlined in the ACG guidelines: Patients with moderate to severe disease are treated with prednisone mg daily until resolution of symptoms and resumption of weight gain (generally 7-28 days). Controlled-release oral budesonide formulations at a dose of 9 mg daily have been demonstrated to be more effective than placebo or mesalamine 4 g orally daily and have similar efficacy when compared with conventional oral corticosteroids for the treatment of disease in patients with mild moderately active CD involving the distal ileum and / or right colon. The use of anti-tnf monoclonal antibodies, infliximab, adalimumab, and certolizumab pegol, are effective in the treatment of moderate to severely active CD in patients who have not responded despite complete and adequate therapy with a corticosteroid or an immunosuppressive agent. Infliximab monotherapy and infliximab combined with azathioprine are more effective than azathioprine in the treatment of patients with moderate to severe CD who have failed to respond to first-line therapy with mesalamine and / or corticosteroids. In adalimumab, the standard dosing of 40 mg every other week subcutaneously is administered after a loading dose of 160 mg sq initially then 2 weeks later 80 mg sq is given. This maintenance dose of 40 mg every other week is effective to maintain response and remission in patients who respond to the initial induction dose. It has been formally demonstrated that dose escalation to 40 mg weekly may be necessary to maintain response and remission. Certolizumab pegol, 400 mg subcutaneously, has also been effective at inducing and maintaining clinical response and remissions. If a patient has initial benefit with certolizumab pegol and loses response, there is controlled trial data to show benefit for the addition of a single 400 mg sq dose at 3 weeks after the last dose and then to resume every 4 weeks administration of continued certolizumab pegol. Similarly, with infliximab, initial dosing of 5mg/kg every 8 weeks is administered after a loading dose of 5mg/kg at 0, 2 and 6 weeks. Dose escalation to 10 mg/kg or shortening of the dosing interval to a maximum of every 4 weeks has been demonstrated to be an effective strategy to overcome loss of response. If response is lost the frequency of administration is initially shortened to a maximum of every 4 weeks. There is controlled trial noting that individuals who have lost response to infliximab or develop adverse events precluding their ability to continue receiving infliximab will gain benefit from either adalimumab or certolizumab pegol. There is uncontrolled data that suggest that individuals who have either a loss of response or adverse event that precluded further use to two anti-tnf agents can gain benefit from use of a third Anti-TNF agent. The anti-alpha 4 integrin antibody, natalizumab, is effective in the treatment of patients with moderate to severely active CD who have had an inadequate response or are unable to tolerate conventional CD therapies and anti-tnf monoclonal antibody therapy. Infliximab, adalimumab, and certolizumab pegol can be used as alternatives to steroid therapy in selected patients in whom corticosteroids are contraindicated or not desired. It remains to be determined whether thiopurines or methotrexate will be advantageously used as concomitant therapy with infliximab, adalimumab or certolizumab pegol once these biologics have been used as initial therapy and the patient has had an inadequate response. CyA has not been demonstrated to be efficacious for induction and maintenance of remission in patients with CD. Methotrexate has been demonstrated to be effective therapy for induction of remission, allow steroid withdrawal and maintain remission in patients with CD who require steroid use. Immunogenicity There are three potential strategies that can be used either alone or in combination to lessen the immunogenicity expressed toward anti-tnf agents and thus lessen the potential for drug resistance. (1) Concomitant administration of an immunosuppressive agent (e.g., AZA, 6-MP, or methotrexate) with anti-tnf therapy has been demonstrated to reduce immunogenicity. Ideally, the immunosuppressive agent should be started well in advance of the first anti-tnf agent s administration. This practice, however, is not always possible. Symposium B: Clinical Challenges in IBD A Case-based Approach 107

5 (2) Administration of induction dosing of anti-tnf therapy (infliximab at 0, 2, and 6 weeks; adalimumab 160 mg at 0 and 2 weeks; and certolizumab pegol 400 mg sq at 0 and 2 weeks), followed by maintenance anti-tnf therapy thereafter (infliximab 5mg/kg every 8 weeks, certolizumab pegol 400 mg sq every 4 weeks and adalimumab 40 mg sq every 2 weeks) is associated with a lower prevalence of antibody formation. And also (3) Premedication with intravenous hydrocortisone, 200 mg has been demonstrated to be an approach to reduce the immunogenicity of infliximab. Drug levels and immunogenicity data may help guide therapy with AntiTNF therapy. Recent preliminary data suggests that patient with low level antibodies and low drug levels may respond to AntiTNF therapy dose escalation; patients with low drug levels and no antibodies respond to AntiTNF dose elevation; whereas those patients with high level antibodies and low drug levels do not respond to drug dose intensification. Other Issues: Non-adherence / Paradoxical Responses / NSAIDs / Cigarettes Non-adherence to the prescribed medical regimen should be investigated in all refractory patients. The prevalence of non-adherence to medical therapy in IBD patients has been reported to range from 40-60%. Lack of compliance has been associated with relapse among UC patients previously in remission. Patients associated risk factors that have been incited as risk factors for non-adherence include: male gender, single marital status, and psychiatric disorders, and treatment-related factors, including multiple medications, frequent dosing intervals, side effects and expense. Direct interrogation of patients about adherence is important, because this information is frequently not voluntarily revealed; however, even with direct questioning this information may not be revealed. In specific scenarios when suspicion for noncompliance is high, measurement of urinary salicylate levels and erythrocyte 6-thioguanine nucleotide levels can serve as surrogate markers for 5-ASA agents and purine analogue ingestion, respectively. It is also to search for potential intolerance to medications such as sulfasalazine and mesalamine derivatives. Sulfasalazine and other 5-ASA drugs account for most adverse events reported but these typically resolve after drug discontinuation. Patients intolerant to one particular 5-ASA formulation may tolerate another 5-ASA medication. In general, it is recommended to avoid the use of NSAIDs in treatment of patients with IBD. There are numerous cases and case series in the literature of patients flaring with their use who have CD or UC. Additionally, patients with CD who are smoking and quit smoking are less likely than those people who continue smoking to require corticosteroids or immunosuppressives. Thus, all CD patients are encouraged to quit smoking. In patients with UC, smoking cessation may actually worsen the course of disease. Smoking cessation has been associated with increased disease severity, more frequent need for hospitalizations and a higher need for use of steroids or immunosuppression. Although resumption of smoking may have a beneficial effect the deleterious risks make this practice not advisable. Conclusion Many different factors may lead to a patient having refractory IBD. In evaluating the presence of refractory IBD, a systematic approach needs to take place. It is critical to accurately diagnose the specific type of IBD present, define the extent of disease and also assess disease activity. It is important to assess for the presence of complications including stricture, abscess and fistulas and treat them appropriately. Enteric infections that simulate active disease or exacerbating disease activity need to be searched for. Optimization of medical therapy is critical when treating patients with IBD. Be cognizant of drug intolerances and paradoxical side effects that may occur. If an expected response does not occur, evaluate for adherence. Consider surgery when disease remains refractory despite optimal medical management. References 1. Bartlett JG, Gerding DN. Clinical recognition and diagnosis of Clostridium difficile infection. Clin Infect Dis 2008;46 (Suppl 1):S12-S Ticehurst, JR, Atird DZ, Dam LM, et al. Effective detection of toxigenic Clostridium difficile by a two-step algorithm including tests for antigen and cytotoxin. J Clin Microbiol 2006;44: Stamper PD, Alcabasa R, Aird D, et al. Comparison of a commercial real-time PCR assay for tcdb detection to a cell culture cytotoxicity assay and toxigenic culture for direct detection of toxin-producing Clostridium difficile in clinical samples. J Clin Microbiol 2009;47: Kvach EJ, Ferguson D, Riska PF, Landry ML. 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