Slide Lecture with Audio
This activity is based on a 45-minute slide lecture presented by Dr. Jonathan A. Leighton and Dr. Randolph V. Fugit. This program is available as read only and with accompanying audio.
*Scroll to read lecture and/or follow along with audio.
Slide 1: Welcome to the teleconference, “Patient-Centered Advances in the Management of Crohn’s Disease.” This program is jointly sponsored by Medical Education Collaborative, Inc and Princeton CME and is supported by an educational grant from Abbott Laboratories.
This activity is designed to educate pharmacists, gastroenterologist nurses, and case managers on the clinical and economic burden of Crohn’s disease and the effect of this disease on patient quality of life. Through the utilization of available treatment strategies, including conventional pharmacologic and surgical approaches, as well as emerging biologic therapies, disease remission may be induced and maintained resulting in optimal patient outcomes.
Slide 2: After completing this activity, participants should be able to:
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Discuss the clinical and economic burden of Crohn’s disease, including the effect of disease on patient quality of life
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Outline the benefits and limitations of conventional pharmacologic and surgical approaches for the treatment of Crohn’s disease
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Evaluate the potential impact of emerging biologic therapies for the management of refractory Crohn’s disease
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Utilize available treatment strategies to induce and maintain remission of Crohn’s disease for optimal patient outcomes
Medical Education Collaborative, Inc (MEC) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. This continuing nursing education activity for 1.0 contact hour is provided by MEC. MEC is approved by the California Board of Registered Nursing, Provider Number 129909, for 1.0 contact hour. For questions regarding the ANCC accreditation of this activity, please contact MEC at 866-420-3252.
Princeton CME is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (ACPE provider #452) and complies with the Criteria for Quality and Interpretative Guidelines. This activity is approved for 1 contact hour (0.1 CEU) of continuing pharmacy education (UPN 452-999-08-019-H01-P).
This activity is approved for 1 hour of continuing education credit for case managers by the Commission for Case Manager Certification (CCMC).
Slide 3: Presenting today is Dr. Jonathan A. Leighton, Professor of Medicine and Chair, Division of Gastroenterology and Hepatology at Mayo Clinic in Scottsdale, Arizona. A case study applying the data to a real-world scenario will be presented by Dr. Randolph V. Fugit, Internal Medicine Specialist at Denver Veterans Affairs Medical Center and Adjoint Assistant Professor, Pharmacy Practice at the University of Colorado Health Sciences Center in Denver, Colorado.
Faculty disclosures for this activity are as follows—
Dr. Dudley-Brown is a speaker for the Crohn’s and Colitis Foundation of America.
Dr. Fugit is a consultant for Pfizer, Inc. He receives grant/research support from Pfizer, Inc and is on the speakers bureau for Boehringer Ingelheim Pharmaceuticals, Cubist Pharmaceuticals, Pfizer, Inc, and sanofi-aventis U.S.
Dr. Leighton is a consultant for Given Imaging, Procter & Gamble, and NPS Pharmaceuticals. He receives grant/research support from Abbott Laboratories, Bristol-Meyers Squibb Company, Given Imaging, Otsuka America Pharmaceuticals, and Procter & Gamble.
Ms. Skinner is on the speakers bureau for Boehringer Ingelheim Pharmaceuticals, Bristol-Meyers Squibb Company, Forest Pharmaceuticals, Inc, Pfizer, Inc, Roche Diagnostics, and sanofi-aventis U.S.
Dr. Behm disclosed no relevant financial relationships with any commercial interest.
Please remember that to receive continuing education credit, following the conclusion of this activity each participant must complete the post-test and evaluation form. These forms can be easily completed online at www.princetoncme.com.
Thank you again for joining us. Dr. Fugit will now begin his presentation.
Slides 4 & 5: Thank you. Our patient today is a 29-year-old female who presents to her physician complaining of significant continuous, right-lower-quadrant abdominal pain. She describes her symptoms as occurring “on again, off again” initially; however, over the past few weeks, they have increased in frequency and now remain pretty much constant.
She describes the quality of her pain to be crampy in nature that increases in intensity with meals and is somewhat relieved by bowel movements, which have unfortunately increased dramatically over the past month and now have been occurring up to 6 times per day. She states she is very lethargic, tired, and does not feel like eating and has lost approximately 20 pounds in the past month. She presents now very weak-looking, sickly, and pale.
Slide 6: On the next slide, we continue our patient presentation. Her medical history is pretty much noncontributory. She had her appendix removed 17 years ago, which helps effectively rule out the presence of acute appendicitis in this patient presenting now with right-lower-quadrant pain.
Her current medications include famotidine 20 mg twice daily for reflux symptoms, which are undiagnosed at this point in this patient. And, she also takes a daily birth control pill. She does currently smoke about 2 packs per day for the past 10 to 12 years and denies any alcohol or drug abuse.
Upon physical examination, the patient describes acute tenderness, especially upon palpation of the lower right quadrant of the abdomen, and the presence of a mass there has been identified.
Slide 7: On the next slide, continuing with our patient presentation, the patient is normotensive with normal/high-normal heart rate. She is slightly febrile with a low-grade fever. She is currently anemic, with a hematocrit and hemoglobin at 29% and 10.2 g/dL, respectively. Her white blood cell count is elevated, as is her erythrocyte sedimentation rate, suggesting an infectious or inflammatory process. Her stool is also positive for occult blood.
Slide 8: On the next slide, continuing with our patient presentation and her evaluation, the patient underwent both radiographic and endoscopic examinations. An air contrast barium enema revealed areas of edema involving the terminal ileum and the ileocecal valve. There are also small ulcerations identified on irregular-appearing nodules with the presence of areas of normal-appearing intervening mucosa. Upon endoscopy, the patient was determined not to have true colonic involvement. However, within the terminal ileum, ulceration was identified with “cobblestone”-appearing mucosa. Once again, an important finding of involved mucosa interspersed with normal mucosa was identified, the so-called “skip lesions.”
Based on evaluation and laboratory findings, this patient was then diagnosed with mild-to-moderate Crohn’s disease.
Slide 9: So while you are listening now to the main presentation, some questions for your consideration to ponder about our case are: What are the most appropriate agents to induce remission in this patient with Crohn’s disease? Second, once remission is achieved in this patient, what available pharmacologic agents are most effective in maintaining remission? And finally, when would it be appropriate to consider the addition of a biologic agent to this patient’s pharmacotherapy plan?
I will now turn things over to Dr. Leighton for his presentation.
Slides 10 & 11: Thank you, Dr. Fugit. I am Dr. Leighton, and I would like to begin our presentation today with an overview of the clinical and economic burden of Crohn’s disease.
Slide 12: Let’s first look at the clinical and economic burden that we often see in our patients. Crohn’s disease is associated with a significant clinical burden. It is very important to understand and communicate to our patients, as well as their families, that Crohn’s disease is, in fact, a chronic and life-long disorder and in most cases will not go away on its own.
It affects approximately 500,000 individuals, equally between males and females. The clinical course is characterized by a waxing and waning pattern with periods of remission alternating with relapse. Most important, there is no known cure, and that is why medical therapy is so important.
Slide 13: The economic burden of Crohn’s disease is also significant. In the United States, it is clear that the economic burden of Crohn’s disease is in the range of $10.9 billion to $15.5 billion based on 2006 figures. Factors contributing to the direct medical costs of healthcare expenditures—and you can see these dollar amounts in the slide—include frequent physician visits, the chronicity of Crohn’s disease, as well as complications requiring hospitalization and surgery.
Slide 14: Indirect costs are also significant and need to be understood. And, as you can see by the dollar figures, these indirect costs account for approximately 28% of the total costs. This reflects the high prevalence of Crohn’s disease among working-age individuals. Indirect costs are attributed to absenteeism, reduced work productivity, and also loss of leisure time.
Slide 15: Quality of life is one important way to measure the impact of Crohn’s disease on our patients. The effect that Crohn’s disease has on its sufferers is frequently devastating and is most often severely underestimated. Although Crohn’s disease may not significantly shorten the life expectancy of sufferers, these patients having fallen ill early in their life, are subject to a lifetime of suffering with chronic pain, diarrhea, severe limitations in their social and family lives, frequent hospitalizations, surgeries, and an overall severely reduced quality of life. The emotional damage of Crohn’s disease is believed to be almost as destructive as the disease itself, with depression frequently occurring due to an inability to lead a normal life.
Slide 16: This next slide on quality of life shows that it is also important to realize that nearly 50% of patients are diagnosed with another condition before being diagnosed with Crohn’s disease. This uses precious time that could be used to treat the patient; therefore, early diagnosis is critical. It is also important to realize that nearly 70% of patients with Crohn’s disease require hospitalization at some time over a 5-year period, which further impacts quality of life. And, studies show that effective treatment of active Crohn’s disease can improve this quality of life.
Slide 17: So now let’s focus on the clinical presentation of Crohn’s disease, which can be quite varied based on the type of disease that each patient has.
Slide 18: The 3 major categories or clinical features associated with Crohn’s disease are those related to inflammation, obstruction, and fistualization. Chronic diarrhea, abdominal pain, and tenderness are among the most common presenting symptoms. Inflammatory symptoms also include rectal bleeding and weight loss. But during the evolution of chronic Crohn’s disease, the bowel can develop recurrent obstructions, giving rise to symptoms of cramps, distension, constipation, and/or vomiting. The disease can also proceed to abdominal fistula, often producing pain, chills, and fever with possible abscess formation and general wasting. There are 4 main types of fistula, as you can see in the slide. And, it is important to realize that obstruction and fistualization often require surgery to repair.
Slide 19: As physicians and allied health staff, it is also important that we are able to identify and document disease severity. Although there is no perfect disease severity scale, the one shown in this slide is fairly accurate. We usually try to classify severity into mild-to-moderate, moderate-to-severe, or severe-to-fulminant. By classifying the disease severity, this often helps to determine the best medical approach for our patients.
Slide 20: This next graph looks at the cumulative probability of a relapse-free course in patients with Crohn’s disease. Ultimately, it is important to realize that the cumulative probability of a relapse-free course in our patients declines significantly with time. At 1 year, you can see that approximately 40% will have at least 1 relapse, and by 3 years, 80% will have a relapse. Again, this is another reason that medical therapy is so important.
Slide 21: The probability of surgery also increases with time, as you can see in this next slide. Regarding the cumulative rate of intestinal resection, you can see that it was 44%, 61%, and 71% at 1, 5, and 10 years, respectively, after diagnosis. Three of 4 patients with Crohn’s disease will undergo an intestinal resection at some time; half of them will ultimately relapse. The extent of disease at diagnosis and the presence of the perianal fistulas have an impact on the risk of surgery and the risk of postoperative recurrence. Women run a higher risk of postoperative recurrence than men, for reasons that are not entirely clear. And, the frequency of surgery has decreased over time, but the postoperative relapse rate remains unchanged.
Slide 22: So as I have mentioned, medical therapy is extremely important. The first-line medications are the 5-ASA medications. The first one used was sulfasalazine, and then the other 5-ASA analogues are listed also. Corticosteroids are also quite effective for inducing remission, but they are not medications we would choose to give our patients if we can avoid them because of side effects. Antibiotics are also useful and can sometimes be used for mild flares, avoiding the need for steroids. The next group of medications you can see are the immunomodulators, which more specifically target the immune system and are very effective for moderate-to-severe disease. And finally, the biologic agents even more specifically target molecules in the immune system, as we will discuss in the following slides.
Slide 23: This next slide reviews the step-up treatment pyramid. Historically, the step-up approach to treatment has been used, with therapy being chosen based on the progressive severity of disease. This diagram summarizes this conventional approach where treatments typically used are based on each level of severity. Aminosalicylates or antibiotics at the bottom, for example, are the treatments of choice for mild disease, with corticosteroids, immunomodulators, and/or biologics being reserved for more moderate-to-severe or even refractory disease. As we will see in a moment, this paradigm may be evolving.
Slide 24: Now, let’s look at the conventional pharmacologic therapies for Crohn’s disease.
Slide 25: 5-ASA medications, as I mentioned, are considered first-line therapies for Crohn’s disease. As I mentioned earlier, sulfasalazine was the first 5-ASA medication used. It is coupled with a sulfa moiety, and the benefits are that it has modest efficacy mainly when Crohn’s disease involves the colon, but does not work as well for Crohn’s disease involving the small bowel. Limitations include lack of efficacy in the small bowel, and up to a 30% adverse effect rate, which is dose-related and also due to the sulfa moiety.
Slide 26: This graph illustrates the dose-dependent response and toxicity associated with sulfasalazine. The clinical response to sulfasalazine is dose-dependent, meaning the more that you give, the better it works. However, this dose-response relationship is compromised by the fact that the toxicity of sulfasalazine is also dose-dependent. As mentioned, up to 30% of the patients taking sulfasalazine have reported adverse reactions to the sulfa moiety, including anorexia, headaches, nausea, gastrointestinal distress, and oligospermia, the latter of which appears to be reversible with sulfasalazine cessation.
Slide 27: This next slide reviews the newer 5-ASA medications that do not have this sulfa moiety. The adverse effects, therefore, are not dose-related while there is dose-related efficacy. In fact, the side effect profile of these oral 5-ASA medications has been shown to be similar to that of placebo. Thus, doses of oral mesalamine can be titrated higher than can equimolar doses of sulfasalazine. Approximately 80% of patients who cannot tolerate sulfasalazine can tolerate mesalamine or 1 of the other 5-ASA medications.
The main limitation is that the efficacy data for these drugs with Crohn’s disease, unlike ulcerative colitis, is inconclusive. There are studies to suggest that they are no better than placebo. They are likely of no benefit in maintaining remission after steroid therapy and are definitely not helpful in severe disease.
Slide 28: This table summarizes those findings. As you can see on the right, 5 out of 8 studies did not show a significant benefit of the 5-ASA medications in maintaining a medically induced remission in Crohn’s disease.
Slide 29: The next group of medications to discuss are the corticosteroids. Corticosteroids are excellent for inducing remission in active, moderate-to-severe Crohn’s disease because they have a rapid onset of action and are relatively inexpensive. It is important to consider osteoporosis prophylaxis, however, when using these medications.
The limitations include the fact that they do not appear to have significant long-term benefits. They have numerous side effects, and many patients will become steroid-dependent after 1 year of treatment.
Slide 30: This study illustrates some of those points with oral prednisolone. One can see that 48% will achieve remission and 32% will be improved at 1 month. However, at 12 months, a significant number will relapse and only 26% are in remission at 12 months.
Slide 31: One can find the same basic findings with oral prednisone. Although it works well for inducing remission at 1 month, this study shows that at 12 months, 28% were steroid-dependent and 38% required surgery. For these reasons, as well as the associated toxicities, steroids are not used long term for maintenance therapy in Crohn’s disease.
Slide 32: Budesonide is a steroid that was developed to help with some of the problems seen with the corticosteroids. It is indicated for distal small bowel and/or proximal colonic Crohn’s disease. It has fewer adverse effects and less adrenal suppression. However, it may be somewhat less effective than oral prednisone. It also is not considered an option for maintenance therapy in most patients.
Slide 33: As this study reveals, in active Crohn’s disease, the budesonide at 9 mg per day was shown to be superior to placebo and 4 mg per day mesalamine or 5-ASA in achieving remission of active Crohn’s disease. Although prednisolone produced remission in a larger percentage of patients than did budesonide, at 8 weeks the difference was not statistically significant. Furthermore, a significantly larger percent of the patients taking prednisolone experienced corticosteroid-associated adverse effects. At 8 weeks, more than twice as many patients in the prednisolone group than in the budesonide group experienced such side effects.
Slide 34: In this maintenance of remission study, patients with symptomatic remission were randomized to receive budesonide 6 mg per day, budesonide 3 mg per day, or placebo. The median times to relapse or discontinuation were 178 days for patients taking 6 mg of budesonide, 124 days for the 3-mg group, and 39 days with placebo. By 1 year, however, relapse rates were similar for all 3 groups and there were no significant between-group differences in changes in quality-of-life assessments, again, confirming that it is not indicated for maintenance therapy.
Slide 35: Let’s now look at antibiotics for Crohn’s disease. As I mentioned earlier, antibiotics are definitely useful in mild, and maybe even moderate, Crohn’s disease. Metronidazole and ciprofloxacin are the ones most commonly used. They also work well for fistulas and small abscesses. These benefits have to be balanced by the potential adverse events that are listed on the right side of the slide, and patients should be made aware of these potential adverse effects.
Slide 36: In the step-up approach to therapy for Crohn’s disease, the immunomodulators are the next class of drugs to discuss. And based on step-up therapy, if 5-ASA medications are not working, then immunomodulator therapy with either azathioprine or 6-MP should strongly be considered. They are effective for maintaining remission and also for treating fistualizing disease.
The potential limitations are the fact that they have a slow onset of action of 3 to 6 months, so they are not useful in inducing a rapid remission. And also, they are not tolerated by approximately 15% of patients. Patients also have to be monitored for potential toxicity.
Slide 37: This study evaluated azathioprine for maintenance of steroid-induced remission in patients with Crohn’s disease. As you can see, the azathioprine group did much better than the placebo group out to 15 months.
Slide 38: Methotrexate is another immunomodulator that can be used in Crohn’s disease. It is usually used when 6-MP or azathioprine is not effective or not tolerated. Studies suggest that it is only effective when used intramuscularly and not orally. It may have a slightly faster onset of action and has been used for remission and maintenance therapy. Data on oral use, unfortunately, is sparse.
Slide 39: This next slide focuses on methotrexate for induction of remission of Crohn’s disease. This study looked at 141 patients who had active Crohn’s disease despite at least 3 months of prednisone. The patients were randomized to receive 25 mg of IM methotrexate or placebo once weekly for 16 weeks. They also received 20 mg daily of prednisone, which was then tapered over 10 weeks except in cases of worsening disease. As you can see, at 16 weeks, the rate of remission was significantly higher in the methotrexate group than the placebo group. The remission rate was also significantly higher with methotrexate than with placebo among patients who received more than 20 mg per day of prednisone as opposed to lower dosages.
Slide 40: Cyclosporine is another immunomodulator that can be potentially used in refractory Crohn’s disease, although it is not used very often. Open-label studies using cyclosporine IV suggest that it is effective for acute steroid-refractory Crohn’s disease as well as fistualizing disease. Unfortunately, low-dose oral cyclosporine does not appear to be effective, and there is no evidence of long-term efficacy. Biologic therapy seems to be, overall, more effective than cyclosporine. The other issues with cyclosporine are the adverse effects that also need to be considered.
Slide 41: It is important to review these adverse effects with all of the immunomodulators, as you can see in this next slide. Although immunomodulator therapy is effective, the adverse effects always need to be considered and communicated to patients. As with any medication, the benefits versus the risks always need to be weighed. With 6-MP, azathioprine, and methotrexate, it is generally felt that the benefits outweigh the risks for moderate-to-severe Crohn’s disease. As you can see from the slide, however, all of the immunomodulators have potential adverse effects that require monitoring. For that reason, blood tests need to be performed on a regular basis and any new symptoms on these medications need to be evaluated immediately. Lymphoma risk, although small, is a definite concern that is currently being evaluated.
Slide 42: In addition to the medical therapy I just reviewed, some patients with Crohn’s disease, unfortunately, do require surgery.
Slide 43: Usually, the goals of surgery are to control symptoms not responding to medications. But whenever surgery is performed, it is critically important to preserve as much small bowel as possible. There are many indications for surgery, but most often it is for obstruction due to strictures or for fistula and/or abscesses. Surgery, however, is not a cure for Crohn’s disease.
Slide 44: This graph shows that the need for surgery in Crohn’s disease does correlate, to some degree, with disease location. In fact, patients with ileocolonic Crohn’s have the highest rates of surgery, whereas those patients with colonic Crohn’s disease have the lowest rates.
Slide 45: This next slide examines the postsurgical recurrence of Crohn’s disease. As I mentioned earlier, surgery is not a cure for Crohn’s disease. In fact, it has been well-documented that postsurgical occurrence in the remaining bowel is extremely common. This study shows that evidence of recurrence based on radiology and endoscopy approximates 90% at 5 years, and symptomatic occurrence occurs in 50% by 5 years. This is why postoperative prophylaxis with medication for patients with aggressive Crohn’s disease is so important. Therefore, patients who undergo surgery will require medications afterward to prevent any recurrence.
Slide 46: Unfortunately, even with the medications I have reviewed and with surgery, there are many patients who still require additional therapy. Biologic therapy, which we will review now, has really revolutionized the treatment of moderate-to-severe Crohn’s disease.
Slide 47: The main class of biologic agents are those that are directed against tumor necrosis factor, or TNF, a proinflammatory cytokine. These drugs are therefore called anti-TNF agents. These agents are monoclonal antibodies that are directed against TNF. This table reviews the current biologic anti-TNF agents approved for Crohn’s disease. These agents have all been evaluated in double-blind, placebo-controlled, randomized trials. Infliximab is a monoclonal antibody that is both mouse and human and is given intravenously. Adalimumab and certolizumab pegol are humanized antibodies that are given subcutaneously.
Slide 48: Infliximab was the first anti-TNF agent approved for Crohn’s disease in 2003. It is a chimeric antibody, meaning that it is both human and mouse derived. It is effective for inducing and maintaining remission in patients with moderate-to-severe Crohn’s disease, as well as fistualizing disease.
Slide 49: In the initial open-label clinical trial using a single infusion of infliximab 5 mg/kg for refractory Crohn’s disease, you can see that the 4-week response and remission rate was statistically significant in favor of infliximab compared to placebo. Following this, the ACCENT 1 study, not shown in this slide, looked at maintenance therapy using infliximab every 8 weeks in 573 patients and showed that patients were more likely to be in remission at weeks 30 and 54 and maintain their response with infliximab maintenance therapy. An endoscopic substudy also showed that scheduled infliximab maintenance therapy resulted in greater improvements in mucosal ulceration, mucosal healing, and less hospitalization.
Slide 50: Infliximab, therefore, was shown to be effective for maintaining remission. It is important to realize that approximately one third of patients with Crohn’s disease, however, will develop fistulas at some point in the course of their disease. The first randomized controlled trial to address fistula healing in Crohn’s disease as the primary end point was ACCENT 2, and infliximab was shown to be significantly more effective than placebo. At week 54, there was complete absence of draining fistulas in 36% of patients receiving infliximab maintenance therapy as compared with 19% of patients receiving placebo. This slide looks at the impact of infliximab on hospitalizations and surgeries in this group of patients. In this ACCENT 2 trial, a retrospective analysis of patients with fistualizing Crohn’s disease treated with maintenance infliximab to achieve remission throughout the course of the 54-week trial is shown in this slide. Again, as you can see, hospitalizations and surgeries were reduced with infliximab maintenance therapy based on the percentage of time in remission.
Slide 51: Now, let’s shift gears for a moment and discuss top-down therapy. As a result of the studies I have just reviewed with you, as well as others, there has been a paradigm shift in the approach to treating aggressive Crohn’s disease. This shift has gone from step-up therapy—which I showed you earlier—to top-down therapy, as shown in this slide. The thought is that if we are going to alter the natural history of Crohn’s disease and prevent long-term complications, then perhaps we should be using biologic therapy earlier in the course of the disease.
In the study shown on this slide, 133 patients were randomized to top-down versus the conventional step-up therapy. As you can see, the results were clearly better with the top-down approach, with the overall treatment success in the top-down group being 29% compared to only 5% in the step-up approach. This study suggests that at least in a subgroup of patients with aggressive Crohn’s disease, earlier treatment with biologic therapy may be indicated.
Slide 52: The second anti-TNF antibody approved for Crohn’s disease was adalimumab, approved for treatment of Crohn’s disease in 2007. It is a human antibody. As previously discussed, infliximab was chimeric, or a combination of human and mouse components. Chimeric antibodies may be more immunogenic and therefore result in human antichimeric antibodies, which then lead to an increase in fusion reactions as well as loss of efficacy of the drug. By creating a fully humanized monoclonal antibody like adalimumab, the evidence suggests that there may be less antibody formation and decreased immunogenicity leading to improved safety with similar efficacy.
Slide 53: The CLASSIC 1 trial, shown in this slide, looked at adalimumab versus placebo for induction of remission in 299 patients with moderate to severely active Crohn’s disease. This trial demonstrated that adalimumab was well tolerated and significantly superior to placebo in inducing remission and response in these patients naive to anti-TNF therapy. You can see that the dose of 160 mg at week 0 followed by 80 mg at week 2 was the most effective for a clinical remission and response.
Slide 54: The CHARM study, shown in this slide, was a double-blind, placebo-controlled trial designed to determine the efficacy and safety of adalimumab 40 mg and looked at adalimumab either weekly or biweekly for maintenance of remission in 854 patients. The percentage of randomized responders in remission at weeks 26 and 56 was significantly greater with both regimens of adalimumab versus placebo. There were no significant differences in efficacy between adalimumab biweekly and weekly, and therefore, the usual starting dose is 40 mg every other week. CHARM also showed adalimumab was associated with decreased hospitalizations and surgeries. This study also showed evidence of fistula response to adalimumab.
Slide 55: It was not known whether another anti-TNF would be effective in someone who did not respond to infliximab. The GAIN study, shown in this slide, was performed in patients with moderate-to-severe Crohn’s disease who had symptoms despite having been treated with infliximab or who were unable to be treated with infliximab because of adverse events. The GAIN study demonstrated that adalimumab was more effective than placebo for induction of remission in patients with either lost response or who developed intolerance to infliximab.
Slide 56: Certolizumab pegol is the third anti-TNF drug that was approved by the FDA in April 2008. It is, again, a humanized monoclonal antibody fragment linked to polyethylene glycol. It, therefore, has a longer half-life than the other agents and is administered subcutaneously once a month.
Slide 57: In the PRECISE 1 trial—a randomized, double-blind, placebo-controlled trial—certolizumab pegol was evaluated in 662 adults. Patients were randomly assigned to receive either 400 mg of certolizumab pegol or placebo subcutaneously at weeks 0, 2, and 4, and then every 4 weeks. As you can see, the trial demonstrated that in patients with moderate-to-severe Crohn’s disease, induction and maintenance therapy with certolizumab pegol was associated with a modest improvement in response rates compared to placebo, as seen in the top graph, but with no significant improvement in remission rates in the bottom graph at weeks 6 and 26.
Slide 58: PRECISE 2, shown in this slide, subsequently demonstrated that patients with moderate-to-severe Crohn’s disease who had a response to certolizumab pegol induction therapy were more likely to maintain the response with certolizumab pegol maintenance therapy at week 26. Incidentally, both PRECISE 1 and 2 were underpowered to determine the efficacy of certolizumab pegol for fistula response.
Slide 59: As with the immunomodulators, the anti-TNF biologic therapies also have adverse effects, listed here, that need to be considered. As far as we know, these adverse effects are similar for infliximab, adalimumab, and certolizumab pegol. In addition to hypersensitivity and immunogenic reactions, infection including tuberculosis and malignancy including lymphoma are most concerning. Monitoring blood tests periodically is therefore indicated. However, available data to date is insufficient for evaluating long-term effects of these agents, and this definitely needs to be studied more thoroughly.
Slide 60: Natalizumab is another biologic agent recently approved for Crohn’s disease with a different mechanism of action. It is a humanized monoclonal antibody to α4 integrin, which is expressed on leukocytes. Alpha-4 integrin facilitates recruitment and migration of leukocytes into the gut tissue, leading to inflammation associated with Crohn’s disease. Natalizumab targets leukocytes to prevent their recruitment and migration, thereby reducing inflammation.
Drug testing, however, was voluntarily suspended in 2005 because of 3 cases of progressive multifocal leukoencephalopathy, a severe neurologic disease. Subsequently, no other cases were identified, and it was recently approved for Crohn’s disease in January 2008 for patients not responding to anti-TNF therapy. Adverse effects include influenza and rare acute infusion reactions. Current evidence suggests it is effective for both induction and maintenance of Crohn’s disease.
Slide 61: In ENACT 1, patients were randomized to receive either natalizumab 300 mg or placebo at weeks 0, 4, and 8 and were evaluated for response at week 10. In ENACT 1, there was a high placebo response rate of 49%, as you can see in the graph on the left. As a result, the response rate expected was not achieved and did not reach statistical significance compared to placebo.
ENACT 2 was a 60-week maintenance follow-up study where patients were randomized to receive either natalizumab 300 mg or placebo every 4 weeks. Patients who continued to receive therapy were significantly more likely to be in remission at the end of week 36 than those on placebo. As you can see on the far right, 44% were in remission versus 26% on placebo. These results suggest that natalizumab is an effective alternative to anti-TNF therapy.
Slide 62: The ENCORE trial looked at response in remission with natalizumab, and as you can see, demonstrated the efficacy of natalizumab as an induction therapy at weeks 8 and 12 compared to placebo.
Slide 63: So now that we have reviewed the specific medical therapies for Crohn’s disease, and also the emerging biologic therapies, it is useful to review the approach to patients who present with Crohn’s disease and the treatment strategies that should be used for our patients.
Slide 64: So when you approach the new patient in your practice, you should always review the differential diagnosis and look for other causes, including infection. Once other causes for inflammation have been ruled out, and the diagnosis of Crohn’s disease is confirmed, then it is important to define the extent and severity of this disease. It is then best to review the goals of therapy and outline what the expectations are for the patient and the family. It is particularly useful if they are given a timeline and plan for therapy, such as, we are going to try this therapy for 2 weeks and if that does not work, then we will move on to therapy X, Y, or Z. It is also critically important to emphasize that this is a chronic disease and that taking the medication is critical to maintain remission even if the patient is feeling well. Otherwise, many times, patients will stop the medication when they are doing better.
Slide 65: Physicians and allied health staff must clearly understand the treatment goals. I also explain to patients that the first goal is to treat the inflammation or induce remission, which will, in turn, relieve symptoms and improve daily functioning. All treatment begins with anti-inflammatories to heal mucosal damage. The second goal of therapy is to achieve and maintain remission using medication, which will, in turn, hopefully prevent complications.
Slide 66: It is extremely important to emphasize the need for maintenance therapy because patients often adhere to therapy for active disease because they are not feeling well, but once the disease is controlled, they are less apt to take the medication. Relapse may occur unless maintenance therapy is continued.
Slide 67: Adherence issues, therefore, in Crohn’s disease are significant. An area that is being studied more and more is that of adherence to medications because it is being realized that many flares of Crohn’s disease may be due to patient nonadherence to the medication. In fact, studies suggest that more than 60% of patients are not adherent to azathioprine and 40% are not adherent to 5-ASA therapy. There are many factors that may contribute to this, including treatment regimen complexity, tablet quantity, and dosing frequency. Drug formulations that consist of less pills and less frequent dosing are currently being studied and appear effective. Finally, intravenous therapies may improve adherence, and a recent trial suggested that only 4% of patients taking infliximab were nonadherent.
Slide 68: So what can physicians and allied health staff do collectively to improve adherence?
The first is to discuss the important of adherence to medications. Also, whenever possible, simplify dosing regimens to once or twice a day and also minimize costs. It is also important to anticipate problems and plan for when they occur. It is important to encourage family member involvement in the patient’s care. If possible, ensure that allied health staff interact frequently with the patients. Patients should also be instructed to call if there is any deterioration in symptoms. And finally, symptoms need to be monitored closely and medications adjusted as needed.
Slide 69: To summarize this presentation, remember that Crohn’s disease is a chronic disease requiring long-term therapy and is associated with significant clinical and economic burden. Also, quality of life is impaired during flare-ups; however, adherence to therapy decreases the risk of relapse. Azathioprine or 6-MP should be considered first-line immunosuppressive maintenance therapy for patients with uncontrolled disease, and methotrexate should be considered second-line immunosuppressive therapy. Anti-TNF therapy should be utilized in those who fail to respond to conventional agents, and if a patient becomes intolerant or allergic to an anti-TNF agent, then an alternative anti-TNF agent or natalizumab should be considered.
Thank you for your time. This concludes my presentation. We will now turn back to Dr. Fugit for a discussion of the case study mentioned at the beginning of this activity. Thank you again.
Slide 70: Thank you, Dr. Leighton. So, back to our case presented at the start of the lecture.
Slide 71: If you will remember, this is a 29-year-old who, based on diagnostic criteria, presented with an initial episode of mild-to-moderate Crohn’s disease. She presented very typically, with abdominal pain, diarrhea, and weight loss. Laboratory analysis proved to show leukocytosis, an increased erythrocyte sedimentation rate, anemia, and occult blood in her stool. And finally, endoscopic and radiologic evaluations showed the disease confined to the small intestines (ileitis).
Slide 72: Looking at our next slide, the chosen treatment regimen for our patient included budesonide 9 mg once daily. Another option in this patient may be prednisone, if cost is a significant issue. Once remission has been obtained, corticosteroids should be slowly tapered. Corticosteroids have not been demonstrated to be an acceptable option in maintaining remission. A nutrition consult has been scheduled for our patient due to the likely malnourishment that occurs in these patients, and specific diets obviously can be implemented and have been shown to actually decrease symptoms associated with Crohn’s disease.
Smoking cessation should occur immediately in our patient, as smoking confers a 2-fold increase in frequency of Crohn’s disease, and Crohn’s disease patients who have actually quit smoking are likely to have a more benign course of the disease compared to those patients who continue to smoke. Interestingly, this is a direct contrast to ulcerative colitis, where smoking has been shown to be partially protective.
The use of an immunomodulating agent should be initiated at this point. Two options include azathioprine 2 to 2.5 mg/kg per day or 6-mercaptopurine at 1 to 1.5 mg/kg per day for maintenance of remission, especially since this patient required corticosteroids to attain remission. Immunomodulatory pharmacotherapy with either of these agents is an acceptable option in hopefully maintaining remission in our patient.
Slide 73: Finally, looking at patient follow-up, the last thing that we should consider, especially in those patients who continue to be symptomatic despite optimized pharmacotherapy as previously described, may be eligible for the use of a biologic agent, also known as the anti-tumor necrosis factor agents. These agents are highly effective in maintaining remission, as discussed in the previous lecture. However, as these are significant immunosuppressant agents, risk versus benefit must be considered prior to initiation. Infliximab 5 mg/kg per dose IV given at weeks 0, 2, and 6, and then every 8 weeks thereafter. The dose can be increased to 10 mg/kg per dose in those patients refractory to the previous dose. Adalimumab 160 mg subcutaneously given as a loading dose at week 0, then at 80 mg at week 2, 40 mg at week 4, and then every 2 weeks thereafter. Certolizumab pegol 400 mg subcutaneously can be given at weeks 0, 2, and 4, and then every 4 weeks thereafter. And then finally, natalizumab at 300 mg IV every 4 weeks.
It is important to realize that treatment with a biologic agent should be discontinued if the patient has not responded after an adequate trial of this agent. And, you can actually consider treatment with an alternative biologic agent in patients with failure to a previous agent.
Thank you for your time. This concludes my presentation.
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