American College of Gastroenterology 65th Annual Scientific Meeting

Day 1 - October 16, 2000

Inflammatory Bowel Disease Treatment: Effectiveness, Safety, and Adherence

Bret A. Lashner, MD

Introduction

Much has been learned in recent years about the use of old and new therapies for treating inflammatory bowel disease (IBD). New therapies (eg, infliximab) and better monitoring of older drugs (eg, 6-mercaptopurine or azathioprine) have advanced our treatment options for this disease entity. The annual meeting of the American College of Gastroenterology held in New York City from October 16-18, 2000, provided a forum for investigators to continue discussions on both their experiences and the latest insights into therapy for IBD. A symposium conducted during this meeting concentrated on safety and adherence issues regarding IBD therapy. The following report summarizes the key clinical findings presented at that symposium and highlights important podium and poster presentations that further contribute to a better understanding of the challenges facing the physician treating the patient with IBD.

Infliximab: Efficacy and Safety Issues

Stephen B. Hanauer, MD, from the University of Chicago, discussed the effectiveness and toxicity experience with more than 60,000 infusions of infliximab (Remicade) given to patients with Crohn's disease in the United States since the drug was approved for clinical use by the FDA in 1998. Infliximab is a chimeric, monoclonal antibody directed against tumor necrosis factor-alpha (TNF-alpha) that demonstrates a high specificity and affinity to TNF-alpha. Results of a number of studies have suggested a central role for TNF-alpha in chronic intestinal inflammation.

In general, the effectiveness of infliximab in clinical practice has been comparable to that reported in the clinical trials. Thus, a single infusion of infliximab (5 mg/kg) given to a patient with inflammatory-type Crohn's disease can be expected to improve as many as 80% of patients and induce remission in approximately one third of all patients. For fistulous Crohn's disease, 3 infusions given over 6 weeks can be expected to decrease drainage in 70% and completely close fistulas in approximately 50% of cases. Based on the University of Chicago experience with 203 patients with Crohn's disease, infliximab appears to be steroid-sparing.

Investigators from Lenox Hill Hospital and Mount Sinai Hospital in New York, Brown University School of Medicine, Beth Israel Deaconess Medical Center, and the Cleveland Clinic confirmed these response rates in adults and children.^[1-4] Additionally, Chey and colleagues^[5] from the Rochester Institute for Digestive Diseases and Sciences showed that infliximab was effective in 16 of 17 patients treated for ulcerative colitis. Unfortunately, these remarkable findings seem to wane 12 weeks following the last infusion. Whether repeated "maintenance" infliximab infusions or institution of high-dose immunosuppressive therapy at the time of infusion will successfully maintain remission has yet to be established.

Careful selection of patients for infliximab infusion should increase response rates and minimize cost and toxicity by avoiding administration of the drug to patients less likely to respond. Brzezinski and colleagues^[4] from the Cleveland Clinic found that individuals who smoked cigarettes and those not on immunosuppressive medications were less likely to respond to therapy with infliximab, especially patients with inflammatory-type disease. By contrast, Rawlins and colleagues^[6] from the Virginia Mason Clinic failed to confirm a better treatment effect in patients taking azathioprine, 6-mercaptopurine, or methotrexate. Rusche and colleagues^[7] from the Indiana University Medical Center demonstrated a better response rate to infliximab in patients with ileocolic or colonic Crohn's disease vs those with small bowel disease.

The use of infliximab in the appropriate patient populations -- despite issues of cost -- can lead to good savings overall for the healthcare system potentially by decreasing need for gastrointestinal surgery by 15%, the need for endoscopies by 34%, and emergency department visits by 63%.^[8]

Adverse Events

Although clinical trials of infliximab report that up to 15% of patients developed human anti-chimeric antibody (HACA), no differences in adverse effects among treated and placebo groups were found. The rate of HACA-positivity may be diminished by concomitant administration of immunosuppressive therapy. Adverse events were primarily acute, minor, and could be treated during infusion with diphenhydramine or, alternatively, by slowing the rate of infusion. Fortunately, severe antibody-mediated reactions such as asthma, hives, or anaphylaxis are very rare. It is unknown whether antibody-mediated reactions are related to HACA, but it is reasonable to withhold infliximab infusions in patients who are positive for the now commercially available HACA. Serious delayed hypersensitivity reactions, usually characterized by arthritis at least 7 days after the infusion, can be observed in a minority of patients who are reinfused more than 3 months after an initial infusion.

The importance of anti-TNF therapy in Crohn's disease was further underscored by Kim and colleagues^[9] from the Medical College of Wisconsin. These investigators found that thalidomide was effective in patients who could not tolerate infliximab. What is the relevance of thalidomide in this setting? Thalidomide, a teratogen that has recently shown efficacy in the treatment of leprosy, also has anti-inflammatory effects. Another adverse effect associated with infliximab is the apparent development of fibrous strictures in 9% (7/76) of patients within a median of 30 days after the inflammation is successfully treated.^[10]

Research is currently underway to expand the indications for infliximab in the IBD setting to include ulcerative colitis, pyoderma gangrenosum, and ankylosing spondylitis.

6-Mercaptopurine and Azathioprine: The Utility of Metabolite Monitoring

Background and Significance

Immunomodulating agents that suppress the immune system and thus downregulate inflammation, such as 6-mercaptopurine (6-MP) and azathioprine (AZA), are important in the long-term treatment of IBD. What is the rationale for the use of immunomodulators in this setting? The rationale stems from observations implicating immunologic mechanisms in the pathogenesis of IBD.

Ernest G. Seidman, MD, from Sainte Justine Hospital in Montreal, presented the latest findings on the clinical utility of measuring 6-MP and AZA metabolites in patients undergoing treatment for IBD. 6-MP and AZA are now 2 of the most widely used drugs for IBD because of their efficacy in both inducing and maintaining remission and their favorable adverse event profile. Data from 3 studies conducted by investigators at Lenox Hill Hospital confirmed the safety of short- and long-term 6-MP (with the exception of an increased risk of malignancy in patients with sustained leukopenia [WBC < 4000/mm³ for at least 3 weeks]).^[11-13] Approximately 8% of patients on 6-MP or AZA will develop acute pancreatitis and 1% will develop allergy characterized by fever, rash, and abdominal pain. About 10% will develop leukopenia and thus need to have doses adjusted downward. 6-MP and AZA can take up to 3 months or longer to reach efficacy, creating a clinical dilemma in nonresponding patients.

Are patients who fail to respond being inadequately dosed or have they simply not taken the drug long enough to have an opportunity to respond? In previous years, clinicians have escalated the dose until mild leukopenia (WBC < 5,000/mm³) was induced. As compared to patients without leukopenia, leukopenic patients were more likely to respond, more likely to have their dose of steroids reduced, and more likely to be adequately treated for complications of IBD. However, this "crude" measure of drug level is not an acceptable practice because not everyone who is dosed adequately will become leukopenic, and toxic doses could be given before leukopenia develops.

Strategies for Monitoring Therapy

Technology is now available that allows for more accurate dosing of 6-MP and AZA. The technology also offers clinicians the opportunity to find the very narrow window between efficacy and toxicity for these medications. The end products of the metabolic pathways for these immunosuppressants and an important metabolizing enzyme have become very useful in managing patients with IBD (see Figure).

Figure. The metabolic pathway of azathioprine and 6-mercaptopurine.

AZA is converted to 6-MP during the first pass of this drug through the liver. 6-MP is further metabolized to 6-thioguanine (6-TG), the active metabolite that can be measured in blood. 6-TG levels greater than 235 pmols/8x10⁸ cells have been shown to correlate with response to 6-MP. Achkar and colleagues^[14] from the Cleveland Clinic Foundation proposed that 6-TG levels greater than 260 pmols/8x10⁸ cells should be the preferred cutoff for therapeutic effectiveness. Moreover, these investigators demonstrated that 6-TG levels were more strongly associated with response than either immunosuppressant dose or WBC less than 5000/mm³.

6-MP is inactivated by 2 pathways: metabolism by xanthine oxidase and by thiopurine methyltransferase (TPMT). Xanthine oxidase metabolizes 6-MP to the inactive thiouric acid. Patients on allopurinol, a xanthine oxidase inhibitor, should be given immunosuppressants with caution, probably at very low doses. Measuring 6-TG levels would be extremely helpful in such patients. Milk contains xanthine oxidase and patients whose 6-TG levels are low despite relatively high doses of the medication should be advised to minimize milk consumption. 6-MP is also metabolized to the inactive 6-methylmercaptopurine (6-MMP) by TPMT. 6-MMP levels greater than 5700 pmol/8x10⁸ cells have been associated with hepatotoxicity, but transient hypertransaminasemia is seen only in a minority of patients. Immunosuppressive medications need not be discontinued if patients are found to have very high levels of 6-MMP and normal liver function tests, but careful monitoring of liver function is essential.

Dubinski and colleagues^[15] from Cedars-Sinai Medical Center presented their work on 6-TG in the treatment of patients with active Crohn's disease who are found to have very high levels of 6-MMP. These patients have an abnormal metabolism of 6-MP such that too much of the inactive 6-MMP is produced and insufficient 6-TG is produced in order to have a therapeutic effect. Providing 6-TG directly to 9 patients with IBD (6 with Crohn's disease and 3 with ulcerative colitis), Dubinski showed a response in 7 and remission in 6. One patient developed leukopenia and none developed or had recurrence of hepatotoxicity. Alternatively, TPMT activity can be diminished when 5-aminosalicylic acid (5-ASA) products are administered. Markowitz and colleagues^[16] from the North Shore-Long Island Jewish Health System showed that 2 patients with high 6-MMP and low 6-TG could have their metabolite profile improved by coadministering 5-ASA.

Metabolite levels need not be checked in every patient. There are 2 populations, however, for which monitoring metabolite levels could prove extremely important in improving patient care and outcome: 1) Metabolite levels should be checked in patients who fail to respond to immunosuppressive therapy to distinguish the true nonresponders from those who are inadequately dosed and from patients who are not adherent to their medication regimens. Therapy can be changed or abandoned based on the results. 2) Monitoring metabolite levels would be helpful for patients whose remission is being maintained by 6-MP or AZA. The chances of remission being maintained are likely to be greatest when 6-TG levels are within the therapeutic range.

Studies for determining levels of TPMT are also available commercially. TPMT is absent in 1 in 300 individuals and, because of the risk of severe toxicity, immunosuppressive therapy should be avoided in them. Eleven percent of the population has lower-than-normal levels and should therefore have immunosuppressants administered at doses lower than what would be given normally. TPMT levels should be checked in all patients being considered for administration of high-dose oral (6-MP 1.5 mg/kg/day or AZA 2.5 mg/kg/day) or intravenous immunosuppressive therapy. Mahadevan and colleagues^[17] from the Mayo Clinic showed that intravenous AZA given to 9 patients with severely active ulcerative colitis enabled 5 of these patients to avoid colectomy and 3 to achieve remission. All such patients should have TPMT levels measured prior to administration of intravenous AZA.

Pregnancy and Nursing: Safety of Commonly Used IBD Drugs

Bret A. Lashner, MD, from the Cleveland Clinic, discussed the available information on the safety of IBD medications in pregnant women. There is a scarcity of controlled trials in pregnant patients with IBD because of the potential liability associated with this population. Moskovitz and colleagues^[18] from the Mount Sinai School of Medicine in New York reported on 231 pregnancies among 120 patients with IBD. In these pregnancies, there was a 6% occurrence of prematurity, a 21% occurrence of spontaneous abortion, and a 2.6% occurrence of major birth defects; medications were not associated with a poor outcome.

What Do We Know?

There are no IBD drugs listed as Category A (controlled studies in women fail to show a fetal risk). Still, it is generally believed that corticosteroids and all 5-ASA products are safe and should be used if necessary in pregnant women. Steroids are considered Category C drugs (fetal risk unknown; ie, either definite fetal risk in laboratory animals has been shown and no studies in women are available, or no studies in animals or women have been done) and 5-ASA products are considered Category B drugs (some fetal risk in laboratory animals has been demonstrated but either no risk has been found in controlled trials in women or no studies are available). Potentially, sulfasalazine, being a sulfa drug that crosses the placenta and is passed in breast milk, could displace bilirubin from albumin, thereby putting the baby at an increased risk for kernicterus. Fortunately, kernicterus has never been observed in babies of mothers on sulfasalazine and, for this reason, it therefore need not be avoided. Sulfasalazine does, however, competitively inhibit folic acid absorption, and pregnant women on sulfasalazine thus need to be supplemented with folic acid to minimize the risk of neural tube defects. Topical 5-ASA has been shown to be safe during pregnancy.

Considerable controversy exists concerning the use of 6-MP or AZA. Both are listed as Category D drugs, meaning that there is a definite risk to the fetus. Therefore, these agents should only be used if the risk of not treating the mother with these medications outweighs the risk to the fetus. These drugs interfere with purine biosynthesis and are especially toxic to rapidly dividing cells. In laboratory animals, 6-MP and AZA are associated with cleft palate, limb malformations, and ocular abnormalities. In women on these immunosuppressants for organ transplantation or systemic lupus erythematosus, there appears to be no increased risk of congenital abnormalities -- but there is a risk for growth retardation and prematurity. In IBD patients, there are few case series that document prematurity and spontaneous abortions in women who were taking 6-MP and AZA and congenital abnormalities when fathers were taking 6-MP. However, the number of patients in these studies is small and the number of complications observed is exceedingly small as well. Dr. Lashner recommended that, if at all possible, women be switched from 6-MP or AZA to steroids and 5-ASA agents during their pregnancy and then be switched back after delivery.

There is so little information on infliximab in pregnancy that it is listed as a Category C drug. Cyclosporine also is listed as a Category C drug, despite the fact that there is some risk in laboratory animals; there are no studies in women. Metronidazole (Category C) is teratogenic in animals, especially in the first trimester, and should therefore be avoided early in pregnancy. Methotrexate is listed as Category X due to teratogenicity and the general consensus that the risks to the fetus outweigh any benefits to the mother; this drug must be avoided during pregnancy and breastfeeding.

Conclusions: What Should and Shouldn't Be Used to Treat the Pregnant Patient With IBD?

In summary, all 5-ASA products and corticosteroids appear to be safe during pregnancy and nursing. Methotrexate is contraindicated, and all other drugs should be used only if the benefits to the mother outweigh any possible risk to the fetus.

Adherence to Recommended IBD Therapy

Sunanda V. Kane, MD, from the University of Chicago, continued the trend with a discussion on strategies for improving patient adherence to recommended therapy. "Adherence" is a preferable term to "compliance" because the former implies a reciprocal interaction between patient and physician. Adherence can be defined as the extent to which patient behavior coincides with medical advice. In most chronic diseases, including IBD, nonadherence ranges between 25% and 50%. Fully 40% of ulcerative colitis patients do not take sulfasalazine as prescribed. There are many reasons for nonadherence, including too-frequent dosing regimens, excessive medication expense, adverse drug effects, and failure to realize the importance of maintenance therapy (including cancer surveillance colonoscopy) for patients who feel well.

The key to improving adherence to therapy centers on patient education by medical professionals. Fully one third of IBD patients feel the need to seek alternative medical therapy (eg, acupuncture, herbal and nutritional supplements, massage, yoga, meditation). ^[19] Hilsden and colleagues from the University of Calgary reported that alternative medicine advice is often freely dispensed to IBD patients by health food store employees, herbalists, and chiropractors. ^[20] The more the patient is aware of the nuances of IBD and its sequelae, as learned from discussions with his or her physician, the more likely that patient will adhere to therapeutic recommendations.

Also, simplifying oral regimens to twice daily, choosing less expensive medications, insisting on follow-up clinic visits, and encouraging attendance at health talks or support groups are strategies likely to improve adherence. Monitoring prescription refills and drug metabolite levels may be useful, especially in patients who are not responding as expected to therapy.

Conclusions and Implications for Clinical Practice

We have entered a new era in the therapy of IBD. The success of new drugs such as the biologic agent infliximab has driven the pharmaceutical industry to investigate other strategies for interrupting the unchecked inflammatory process that underlies the disease. Drug development in IBD has not yet peaked -- there is much more on the way. Additionally, with immunosuppressive metabolite monitoring we can now better dose patients and follow adherence than we ever could in the recent past. Very directly, new ideas have led to better therapy. And, as our experience has grown, use of potentially toxic agents in pregnancy and nursing has become less uncertain than it once was.

Overall, data presented at the annual meeting of the American College of Gastroenterology show that as our therapeutic options and experience continue to expand, we are significantly improving the care of the patient with IBD.

References

1.     Chusid BG, Blank A, Kaganovskaya M, Korelitz BI. Intravenous Remicade outpatient treatment of Crohn's disease: a personal experience [abstract]. Am J Gastroenterol. 2000;95:2531.

2.     Pittman N, Birnbaum A, Benkov K. Anti-tumor necrosis antibody in children with Crohn's disease [abstract]. Am J Gastroenterol. 2000;95:2505.

3.     Shah SA, Fefferman DS, Farrell RJ, et al. Efficacy and safety of infliximab in 221 Crohn's disease patients [abstract]. Am J Gastroenterol. 2000;95:2640-2641.

4.     Parsi M, Richardson S, Achkar J-P, et al. Non-smoking and concurrent immunosuppressive use are predictors of response to infliximab in patients with Crohn's disease [abstract]. Am J Gastroenterol. 2000;95:2499.

5.     Chey WY, Hussain A, Ryan C, et al. Infliximab is an effective therapeutic agent for ulcerative colitis [abstract]. Am J Gastroenterol. 2000;95:2530-2531.

6.     Rawlins M, Gelfand MD, Kozarek RA, et al. Does coadministration of immunosuppressive agents alter response to infliximab in Crohn's disease [abstract]? Am J Gastroenterol. 2000;95:2548-2549.

7.     Rusche M, Helper D, Rex D, et al. Factors influencing the efficacy of infliximab in the management of Crohn's disease [abstract]. Am J Gastroenterol. 2000;95:2500.

8.     Rubenstein JH, Chong RY, Cohen RD. Infliximab decreases resource utilization in patients with Crohn's disease [abstract]. Am J Gastroenterol. 2000;95:2499-500.

9.     Kim JP, Emmons JE, Ginion DG. History of previous infliximab response predicts thalidomide efficacy in refractory Crohn's patients [abstract]. Am J Gastroenterol. 2000;95:2532.

10.  Vasilopoulos S, Kugathasan S, Saeian K, et al. Intestinal strictures complicating initially successful infliximab treatment for luminal Crohn's disease [abstract]. Am J Gastroenterol. 2000;95:2503.

11.  Lobel EZ, Xuereb MA, Panagopoulos G, et al. Optimal duration of treatment with 6-mercaptopurine for ulcerative colitis [abstract]. Am J Gastroenterol. 2000;95:2541.

12.  Korelitz BI, Warman JI, Fleisher MR, et al. Short and long term toxicity to 6-mercaptopurine in the treatment of Crohn's disease [abstract]. Am J Gastroenterol. 2000;95:2539.

13.  Rajapakse R, Furr S, Jaramillo-Nieves L, et al. Is there a predisposition to malignancy when leukopenia is sustained during 6-mercaptopurine treatment of inflammatory bowel disease [abstract]? Am J Gastroenterol. 2000;95:2548.

14.  Achkar J-P, Stevens T, Brzezinski A, et al. 6-Thioguanine levels versus white blood cell counts in guiding 6-mercaptopurine and azathioprine therapy [abstract]. Am J Gastroenterol. 2000;95:2291.

15.  Dubinski M, Hassard PO, Kam L, et al. An open label pilot study evaluating the safety, tolerance and efficacy of thioguanine as an alternate therapy in patients failing 6-mercaptopurine [abstract]. Am J Gastroenterol. 2000;95:2532.

16.  Markowitz JF, Daum F. Inhibiting thiopurine methyltransferase (TPMT) activity with mesalamine improves therapeutic 6-mercaptopurine metabolites in children with Crohn's disease [abstract]. Am J Gastroenterol. 2000;95:2542-2543.

17.  Mahadevan U, Tremaine WJ, Johnson T, et al. Intravenous azathioprine in severe ulcerative colitis: a pilot study [abstract]. Am J Gastroenterol. 2000;95:2542.

18.  Moskovitz D, Scherle E, Chapman ML, et al. 5-ASA, metronidazole, ciprofloxacin, prednisone, 6-mercaptopurine and azathioprine use in pregnant patients with inflammatory bowel disease [abstract]. Am J Gastroenterol. 2000;95:2635.

19.  Borum M, Johnson M, Farmer R, Chutkan R. The use of alternative medicine practices amongst patients with inflammatory bowel disease [abstract]. Am J Gastroenterol. 2000;95:2493.

20.  Hilsden RJ, Verhoef MJ, Rapshuk I, et al. What treatments are recommended by complementary medicine providers for inflammatory bowel disease and what are their views on the efficacy and safety of there therapies [abstract]? Am J Gastroenterol. 2000;95:2495

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