Introduction and Case Presentation
DR. JANE ONKEN: Hello, and welcome to this program on ulcerative colitis. I'm your host, Jane Onken, associate professor of medicine at Duke University Medical Center. Joining me today in North Carolina is Dr. Kim Isaacs, professor of medicine at the University of North Carolina School of Medicine and joining us from Chicago is Dr. Sunanda Kane, associate professor of medicine at the University of Chicago School of Medicine.
The topic for today's AGA CME Café discussion is ulcerative colitis. It is estimated that 500,000 to one million Americans suffer with ulcerative colitis. Until recently, few novel therapies had been developed. Most were variations on a theme, such as new delivery systems for mesalamine products, etc. The more we learn about ulcerative colitis and Crohn's the more we realize that these two disorders are not necessarily distinct entities, but at ends of a spectrum of inflammatory bowel diseases with many phenotypic and likely genotypic forms in between.
I'd like to begin today's discussion with a case presentation. A previously healthy 17-year-old high school student presents with a two-month history of bloody diarrhea. He describes as many as 15 stools per day, low grade fevers, abdominal cramping and decreased oral intake. He has lost approximately six pounds. He denies antibiotic use, travel or a family history of inflammatory bowel disease. He denies nonsteroidal use.
On physical examination his temperature is 37.8. His pulse is 104 and his blood pressure is 110/64. His abdomen is soft, flat with mild left lower quadrant tenderness deep palpation but no rebound or guarding. Stool studies are negative for C. difficile enteric pathogens. Laboratory studies reveal a hemoglobin of 10.6, a normal white blood cell count and mildly elevated C-reactive protein of 1.25 milligrams per deciliter. Colonoscopy reveals circumferential mucosal erythema, friability and mucopus extending from the anal verge to the proximal descending colon. Biopsies from the right transverse and left colon all confirm changes of chronic ulcerative colitis.
Dr. Isaacs, how would you classify this patient's disease severity?
DR. KIM ISAACS: I'd be very concerned about this patient. He has a number of systemic symptoms. He's got tachycardia, he has weight loss, he has a poor appetite. He's a least a moderate but verging on a more severe colitis.
DR. JANE ONKEN: Agreed. What about the extent of his disease? His colonoscopy reveals active inflammation confined to the left colon, but his biopsies confirm changes of chronic colitis on the right side as well. Would this have an impact on your choice of therapeutic agent?
DR. KIM ISAACS: It would have an impact on therapy. I really think that if you biopsy evidence of disease in the pancolonic fashion, you need to call that pancolonic disease, even if endoscopically it looks like it's predominantly left-sided. With left-sided disease you could consider topical therapy. But with active inflammation throughout the bowel, I think that you're going to have to include both systemic and topical and clearly, because he's so ill, you're going to be using systemic therapy in addition anyway.
DR. JANE ONKEN: Good. All right. Well, he is in fact started on Asacol (mesalamine) at a dose of 1.6 grams three times daily and prednisone 40 milligrams per day. Within two weeks he reports a dramatic decrease in stool frequency and blood per rectum. His appetite has returned, and he has gained five pounds. Steroids are tapered over the next two months, and he is instructed to continue is Asacol (mesalamine) at a dose of 1.6 grams three times daily.
Six months later he returns complaining of a three-week history of recurrent bloody diarrhea. He denies recent travel. He denies noncompliance, but upon further questioning does admit that he frequently misses the mid-day dose of Asacol (mesalamine). He also tells you his parents caught him smoking and have grounded him for the past month. His physical examination is benign.
Do you think the reduction in Asacol (mesalamine) dose likely played a role in this patient's relapse. Dr. Kane, you have written extensively issues of medical noncompliance in this patient population. Can you share some of your thoughts on what leads to noncompliance, and what as physicians we can do to try to improve compliance?
DR. SUNANDA KANE: Well sure. This is a patient who has a chronic disease who is being left alone and is being asked to take medications three times a day and quite a few pills each time. So patients will forget to take their medicines or they will be too overwhelmed to take medications. It's always the afternoon dose in the middle of the day that they "forget" to take. So even though the pharmacokinetic studies and the clinical trials, while organized in such a fashion to have patients take their medicines tid, really there isn't a good reason in vivo for these patient to actually have to do a tid, so clinically what we do is allow our patients to take their drugs bid which certainly helps them to take them more regularly. They take it in the morning. They take it in the evening when they come home. And it's the same number of pills but just twice a day rather than three times a day. That makes it much simpler for the patient.
The other thing that we like to do is to actually counsel patients about pushing them to even do once-a-day medicine. When they are well, this seems to work out pretty well. So we've done some pilot work to show that over the average of a month's time, that a patient who is taking just once-a-day medicine, if they're taking six to seven tablets or tablets or another formulation of capsules of a 5-ASA once a day, that over a month's time, they still average more total therapy than they would if they were trying to take it BID or TID. So really keeping the regimen simple for the patient is how you are going to best succeed.
The other thing that I like to do with my younger patients, especially those who are living at home, who are with their parents, is have the parents come in and if a patient is being started on a medication have the parents also start taking their medications at the same time as their kids so that there is positive reinforcement that everybody is taking their medicine at that same time sort of together as a family. And if the parents aren't on anything, then they start on a multivitamin or some sort of supplement, so that there is learned behavior there so that their child is watching their parent do the same thing.
DR. JANE ONKEN: Very interesting. What about the use of topical therapy in this age group? Do you find difficult compliance, especially single, young men?
DR. SUNANDA KANE: Well even for single young women the topical therapy is cumbersome, it's very unglamorous. Young people tend to be up later at night than older people and they're going to bed at midnight, one o'clock in the morning and sleeping in and so administering an enema at one o'clock in the morning and then getting up to have a bowel movement at eight a.m. is very disruptive for them. Topical therapy, while on paper looks like the best therapy for somebody who is having urgency and tenesmus, patients are going to do it once, maybe twice and then they're just going to say "forget it," and they're not going to do anything. So I actually asked a patient upfront, "How often or how willing are you to do this, even for a short time? If you give me two weeks of daily therapy, then I can wean you off of them and just increase your oral dose." So I try to contract with the patient upfront. And if they are honest and they say, "Listen, I'm not going to do this," then I just move on and say, "OK, well that would have been the perfect scenario. Let's see what you will do." Certainly college-aged kids in a dorm situation are not going to do it, and it's unrealistic to think that those kids are going to do that.
Management and Hospital Course
DR. JANE ONKEN: A prednisone taper is initiated, and his dose of Asacol (mesalamine) is increased back to 4.8 grams per day. Two weeks later, he says he is no better and, in fact, is now having significant fecal urgency and has had one episode of fecal incontinence. Mesalamine enemas are added to his regimen. His symptoms improve, but as his prednisone dose is tapered his bloody diarrhea returns. Stool studies are again negative for C. difficile enteric pathogens. His exam is benign but he has lost an additional eight pounds over the past month.
His dose of prednisone is increased back to 40 milligrams per day but, within a week, his mother calls to tell you her son continues to do poorly and is now having fever with chills. You advise her to bring him to the emergency room immediately. A CT scan of the abdomen and pelvis is negative for free air or abscess and confirms bowel wall thickening involving the entire colon. Intravenous steroids and bowel rest are initiated. After seven days he has had little or no response. A general surgeon has been following him in the event that total colectomy is required. You meet with the patient and his family to discuss his treatment options.
In this particular instance, topical therapy was added to oral 5ASA agents and prednisone. Despite this, the patient progressed from moderate to severe colitis and was hospitalized for parenteral therapy. What would be your initial approach to patients such as this?
DR. KIM ISAACS: After the hospitalization, looking at a patient like this, I think that I would certainly start IV steroids as was done in the hospital. I'm encouraged that he doesn't have dilatation of his colon on the CT scan but he clearly has severe colitis. If he had dilatation, I'd be worrying about progression to toxic megacolon and maybe earlier surgical intervention. At the point that he's at right now, I would certainly start IV steroids. With the fever and chills, I'd be concerned a little bit about bacterial translocation, and so I'd empirically cover him with enteric-specific broad spectrum antibiotics as well.
I'd watch and see if he does have an improvement in this course. If he does, then we can consider adding an immunosuppressant therapy that may take a long time for action, such as 6-mercaptopurine or azathioprine. However, if he doesn't respond to the IV steroids, I think we're kind of stuck. Our options at that point would be intravenous cyclosporin, intravenous Remicade therapy and surgical therapy. I think each of them has their pros and cons.
DR. JANE ONKEN: Agreed. Do you usually obtain a CT scan when a patient such as this has come to the emergency room?
DR. KIM ISAACS: The first thing that I would do is actually something simpler, is a flat plate of the abdomen looking for thumbprinting, suggesting bowel wall edema, looking for free air and also looking for any dilatation of the bowel. I think the CT scan was not an unreasonable thing to do. He's presenting with fever and chills. Do we have a microperforation that you might pick up better on CT scan? Do we have an abscess going on? We're assuming that this is ulcerative colitis based on his presentation initially, but could we have been dealing with Crohn's colitis, and do we now have an abscess? So I think I'd start off with a flat plate, but in this particular situation with the fever and systemic symptoms, it was not unreasonable to get a CT scan.
DR. JANE ONKEN: And then to follow with the intravenous antibiotics empirically because of the fever and [chills]. That's right
OK, well Dr. Kane, tell us what would your initial approach to patients hospitalized for ulcerative colitis be?
DR. SUNANDA KANE: Well I agree with Dr. Isaacs and Dr. Onken, what they were saying about the flat plate, the assessment. And I think that right from the emergency room that we get a first stool sample for C. difficile. We're having quite an outbreak of it here, at least in Chicago, an epidemic, if you will. And that's caused quite a few people to have worsening symptoms that we've missed. The empiric antibiotics may be broad spectrum but not necessarily include Flagyl or metronidazole and so we do stool cultures right out of the ER too. And we try to avoid narcotics, even if the patient is complaining of "pain." What they're having is cramping and discomfort and we use anxiolytics rather than pain medicines for those patients.
DR. JANE ONKEN: Agreed. I think one of the most difficult aspects of caring for patients such as this, is the request by the patient or the family for pain medication. But obviously we don't want to do anything that would cloud the physical exam and might mask a perforation or other significant complication.
In this particular instance, this patient receives an induction series of infliximab infusions with five milligrams per kilogram at zero, two and six weeks. At his followup clinic appointment, he reports he is feeling much better. He now averages two formed stools per day without gross blood. His parents do accompany him to clinic. They have been reading about ulcerative colitis on the Internet and have questions about their son's long-term prognosis and his risk of developing colorectal cancer. They want to know when he should have his next colonoscopy, and if there is anything he can do to reduce his risk of cancer.
Maintenance Therapy
DR. JANE ONKEN: Let's talk first about maintenance therapy in this patient. I think Dr. Isaacs began or alluded to this earlier. This patient responded to an induction regimen of infliximab. Dr. Isaacs, what would you use as maintenance therapy, as far as maintenance therapy is concerned?
DR. KIM ISAACS: I would try to get him on an antimetabolite, such as azathioprine or 6-mercaptopurine. You're in a good situation right now. He's doing fairly well. The onset of efficacy of these drugs is usually in the range of about three months, four months, and I think that you have the leeway to be able to do that right now. We have long-term experience with these agents in Crohn's disease. They look fairly safe. We're using them more and more in ulcerative colitis. And with the fact that he required fairly aggressive therapy to get into a remission state, I think that immunosuppressive therapy is reasonable at this point in him and that's what I would institute.
DR. JANE ONKEN: Dr. Kane, suppose this patient had been started on IV cyclosporin, what would your maintenance therapy recommendations be?
DR. SUNANDA KANE: So just as Dr. Isaacs said, that the short-term induction with either the anti-TNF or cyclosporin in this case, that he needs to be on a long-term antimetabolite and we would start azathioprine or 6-MP on the day of discharge and wean him off the prednisone first, then stop the cyclosporin and hopefully in that three-month time he's now bridged over to an antimetabolite.
DR. JANE ONKEN: Would you continue his 5-ASA agent?
DR. SUNANDA KANE: I would not. Because he has already proven that his disease activity level has been, you know, to the severe point and 5-ASAs just don't have a role in severe disease. We don't really have a lot of evidence that in conjunction with some of these immunomodulators and immunosuppressants, that they really have an independent role that make it so important to have onboard.
A Closer Look at Colitis
DR. JANE ONKEN: Let's continue on to a more detailed discussion on ulcerative colitis. Dr. Kane, how do you choose a 5-ASA compound for an individual patient?
DR. SUNANDA KANE: So if we're talking about ulcerative colitis, we're talking about some or all of the colon being affected. All of the 5-ASAs that are available deliver medication to the colon in an effective manner. So I ask the patient first, "Do you want a capsule or do you want a tablet?" And they may have a preference right out of the gate. I ask the patients, "How many capsules or tablets do you think you can take in a day?" I also ask them "Do you know if there is on your insurance plan a preferred agent?" Sort of taking those into consideration, that's how I choose. I think that all of the 5-ASAs are efficacious and that if the patient takes them in a regular manner, that they'll achieve clinical results.
DR. JANE ONKEN: Do you ever change from one agent to another. If so, why?
DR. SUNANDA KANE: I do change, and it's not because of efficacy as much as it is for adverse events or side effects. There are certain formulations, like the pH-dependent mesalamine that can give headaches or hair loss. If that's the case, then I will change the patient over to a different formulation. Some patients are very put off by the fact that they can see little micro granules in their stool, so I will change from the time-deponent or moisture-dependent formulation to something else. And so switching from one to another is more because of a patient's specific side effect than what I don't think would be an efficacy issue.
DR. KIM ISAACS: Just one thing to add to that. If a patient can tolerate sulfa, as in sulfasalazine and they have significant joint complaints, we try to use sulfasalazine for that patient population.
DR. SUNANDA KANE: Absolutely. I couldn't agree more. And sometimes, I will add a little bit of sulfasalazine to the regimen just for the joint symptoms along with their other 5-ASA preparation.
DR. JANE ONKEN: Right. And so the interesting point here being that the sulfapyridine moiety may be what is responsible for alleviating some of the joint symptoms. Is that correct?
DR. SUNANDA KANE: That's what we'd like to believe, yes.
DR. JANE ONKEN: Right. Dr. Isaacs, what about the temptation that many physicians have to wean or lower the 5-ASA dose once remission is achieved?
DR. KIM ISAACS: Well, I think that it should be avoided if possible. Usually we try to keep people on the dosing that got them into remission and try to maintain there. But as Susie was talking about earlier with compliance issues, you want to also make sure that you're maximizing your compliance with when you're giving the dose, how many pills you're giving. And if you can ensure that for treatment, we try to maintain the same dose.
DR. JANE ONKEN: Susie, you feel the same?
DR. SUNANDA KANE: I do, and the way I explain it to my patients is like treating high blood pressure. That we start them on a dose of antihypertensive and it gets their blood pressure under control. So why would we switch their dose to something lower when we know that worked and put them into remission.
Therapeutics and Compliance
DR. JANE ONKEN: Do you think that any of the newer 5-ASA preparations, such as the 500 milligram Pentasa tablets or capsules, the multi matrix delivery system for mesalamine or the micro pellet will have an impact on compliance?
DR. SUNANDA KANE: Oh absolutely. I've already noticed that the 500 milligram Pentasa capsule has increased the daily consumption or at least the average over a month consumption of Pentasa for my patients who are on that. The MMX technology, which allows delivery of therapeutic doses of 5-ASAs in a once-a-day regimen is going to be huge.
DR. JANE ONKEN: Right. I agree, particularly for the teenage population or the young adult population that has difficulty fitting in the midday dose, as you alluded to earlier.
DR. SUNANDA KANE: Right. Well you know our IBD population is getting older because they are not going to surgery like they used to and they are living longer. They go on to other medications as they get older so it's nice that they can take their IBD medication once a day and not have to worry about interactions or trying to combine one thing with another.
The Role of Nicotine
DR. JANE ONKEN: What about the smoking issue? In the case we presented earlier, the young man was caught smoking by his parents and grounded, so he clearly had to stop smoking. Do you think it plays a role in the relapse of ulcerative colitis? Susie?
DR. SUNANDA KANE: I do, and it's very interesting. We didn't specify how many cigarettes this young gentleman was smoking, that I believe that the literature supports that you need seven cigarettes or more per day to actually notice a difference or an effect. And certainly we see that ulcerative colitis flares in the ex-smokers and we have actually used nicotine patches as adjunctive therapy…especially our hospitalized patients.
DR. JANE ONKEN: Kim, do you find the same and have you been using the nicotine patches in your patient population?
DR. KIM ISAACS: We do as Susie does. If we have a patient that was a big-time smoker, stopped, has a flare of disease activity, that's the patient population that we put on the nicotine patches. The studies show that the non-smokers, there's really marginal if any benefit and significant side effects.
The Role of Surgery
DR. JANE ONKEN: OK. Let's shift gears a little bit and talk a little bit more about the patient with severe ulcerative colitis that is hospitalized. Susie, how long do you usually wait before you consult a surgeon?
DR. SUNANDA KANE: A surgeon comes onboard usually between 24 and 48 hours after the patient is hospitalized. We give them that amount of time to declare themselves in terms of quick response to IV steroids and just bed rest and to clear their cultures or their stools of any infectious agent. We hate to send a patient to surgery if it's just C. diff. So usually it's 24 to 48 hours.
DR. JANE ONKEN: The caveat to that would be a patient coming in who already has colonic dilatation. That's a true GI emergency and the surgeons need to be onboard from minute one in that patient population. Right?
DR. SUNANDA KANE: Yeah, I agree.
DR. JANE ONKEN: Agreed. How about changing therapy? When would you add cyclosporin to the steroids and if so, what dose would you use? Kim?
DR. KIM ISAACS: We would add cyclosporin usually within about three to four days of looking at their response on IV steroids and if they're not really turning around in three to four days, or if we have a patient that was already on multiple courses of steroids on the outside, we would initiate cyclosporin. The initial trial was with four milligrams per kilogram per day in a continuous IV infusion, but there has since been data that suggests that two milligrams per kilogram per day gives a similar response and maybe with less side effects. So our protocol typically starts with two milligrams per kilogram per day in a continuous IV infusion and then we may dosage increase from that if necessary, depending on levels and depending on response.
DR. SUNANDA KANE: That's pretty much what we do. Four days is going to be long enough to have the patient declare themselves as a steroid responder or not. And in that time, we check a serum cholesterol level and we've discussed with them the other potential side effects to watch for, like seizures and high blood pressure and headaches. So, we've sort of planted the seed, if you will, so the patient feels more comfortable.
DR. JANE ONKEN: Has the efficacy data on infliximab and its time to onset of action and side effect profile in the moderate-to-severe ulcerative colitis patients influenced your choice of therapeutic agent in the patient with severe ulcerative colitis that has failed IV steroids? Susie?
DR. SUNANDA KANE: Oh, well as being a tertiary care referral center, the patients who are transferred to us or the ones that are hospitalized, have already seen at least a week of IV steroids and are not better. We have had very little success with infliximab for our severe ulcerative colitis patients. So we don't usually offer it to patients in this scenario at least. There have been occasions where we have and those are the patients who may have a more moderate case than those who we would consider severe enough to be a cyclosporin candidate. We just haven't had a lot of success with it. And we feel that cyclosporin is a window you can open and close, whereas with Remicade, once you've given it, you sort of shut the door to offering cyclosporin just because of the profound immunosuppression that you'll get.
DR. KIM ISAACS: I would agree with that. We go with cyclosporin in this patient population and our experience is similar to Susie's. In a tertiary center, severe disease, our response rate with Remicade is very low.
DR. JANE ONKEN: OK. Getting back to the surgical consult, clearly surgery is an option and may in fact be a necessity for patients with severe, nonresponsive ulcerative colitis. Do you consider surgery a treatment option for ulcerative colitis patients with moderate disease? Kim?
DR. KIM ISAACS: It depends on their medications and what they require to keep them in remission. If I have somebody that is steroid-dependent despite immunosuppressive therapy, even if they have minimally active disease, but I can't taper off the steroids, yes, I would consider surgery an option. If I can keep a patient in long-term remission who has no contraindications to long-term immunosuppressive therapy, I think that I would not use surgery in that particular patient.
DR. JANE ONKEN: Susie?
DR. SUNANDA KANE: Oh, I agree with Kim. I think that there are patients who, you know, with all our best intentions, have tried on immunomodulators, different immunosuppressants and they don't tolerate them, or they've had such bad side effects or comorbidities that really hurting the patient more than helping them with medicine and that surgery is the right thing to do. There are also a few out there who are just so overwhelmed by the thought of cancer, and maybe in their family they have a strong family history for cancer, that they are just the right candidate for prophylactic surgery because you're afraid that surveying them won't be enough. The patient who has moderate disease and many, many pseudopolyps, I tend to talk about surgery a little bit more than somebody who doesn't have all those pseudopolyps.
DR. JANE ONKEN: In fact, even the patient who is remission who has many, many pseudopolyps, this often comes up as a point of discussion.
DR. SUNANDA KANE: Right.
DR. JANE ONKEN: Susie, in your practice, what do you find are the primary outcomes or the main outcomes, including complications after colectomy for ulcerative colitis?
DR. SUNANDA KANE: We're lucky that we have two very gifted surgeons and so the perioperative period we don't see a lot of complications at all and, in fact, quite a few of our patients are having laparoscopic colectomies and pouch procedures. They have a very low pouchitis rate but it's still around 50% for all comers after one year. I am sorry to say that what we're seeing probably the most of, and again I think it's the nature of our tertiary care center, is that the patients who have been through a pouch procedure and come back a year, and now have fistulas, perianal disease, and really what they had was Crohn's.
Cancer Risk and Surveillance
DR. JANE ONKEN: Right. Which gets back to the earlier point. These are not necessarily two distinct diseases but perhaps ends of a spectrum of inflammatory bowel diseases. In this particular case we presented earlier, the patient's family was obviously very concerned about their son's risk of developing cancer. What do you tell your patients about the relative risk of developing colorectal cancer?
DR. KIM ISAACS: With pancolonic disease, I tell people that at about 10 years of disease, their risk goes up per year about .5 to 1%, starting at about 10 years of disease.
DR. JANE ONKEN: When do you begin surveillance colonoscopy? Do you typically start at that 10 year mark?
DR. KIM ISAACS: We usually do a baseline at around between eight and 10 years, and then depending on extent of disease and also whether they have coexisting PSE, we'll dictate how often we do screen. Usually initially that first 10 year period, we're screening about every two to three years and then at 20 years of disease we're screening annually. With PSE, we start screening at the time of their diagnosis.
DR. JANE ONKEN: Of colitis?
DR. KIM ISAACS: Of colitis.
DR. JANE ONKEN: OK. Susie, same?
DR. SUNANDA KANE: Same thing. Yeah, and we actually have a couple of protocols now where we are using some of the dyes.
The chromoendoscopy are still in research protocols. It's not standard of care yet. And we have a multifocal camera now that can refract certain colors and show us abnormalities so we're looking forward to using some of those new technologies.
DR. JANE ONKEN: Kim, do you add agents such as folate or do you continue 5-ASA agents in patients in order to try to reduce their risk of colorectal cancer?
DR. KIM ISAACS: My thought on the risk of colorectal cancer is that in part it's due to disease activity. I will maintain a patient on a 5-ASA in order to keep their disease quiescent. Now with folate supplementation, we clearly do it with sulfasalazine. I don't necessarily routinely put my other patients on folate. They may be on a multivitamin, but I'm not purposely starting that for colorectal cancer risk prevention. The data for both folate and 5-ASAs are very, very mixed. You can find studies that will land on either side of the spectrum.
DR. JANE ONKEN: Right. Susie, same?
DR. SUNANDA KANE: Same thing and I think, again, it's a discussion with the patient of what medicines they're willing to take and why they're taking them and the mechanisms of action. That patients can get very confused about what they're taking and why they're taking them and to say, "OK, well if you're already on azathioprine or 6-MP well isn't that keeping my disease under control, Dr. Kane?" Then "Yes, well a 5-ASA works not at the bloodstream level but at the level of the lining of your colon and that maybe this will be an added layer of protection, if you will. And there are some data to suggest that it can reduce your risk for colorectal cancer." So you sort of phrase it in that way. There is some data to suggest that maybe it can reduce your risk of cancer, and then the patient with their comfort level will say, "Oh, OK, well it's only going to be two or three extra tablets per day. I can do that," because they're already taking ginkgo biloba and they're taking aloe and garlic and everything else. So what's another three tablets?
Future therapies, Diagnostic Innovations, and Conclusion
DR. JANE ONKEN: Right. We're almost out of time for this session so in closing, I'd like to ask both Drs. Isaacs and Kane whether there are any particular areas of interest that are currently under investigation, either in the form of new therapies, such as apheresis or probiotics or maybe new formulations of old therapies that we talked about, the MMX formulation, or diagnostic tools, such as chromoendoscopy, a genetic testing that you feel are likely to have a significant impact on the way we diagnose and/or treat ulcerative colitis in the near future. Susie?
DR. SUNANDA KANE: I alluded to the chromoendoscopy and the confocal microscopy. I think that's going to help us be able to detect microscopic levels of inflammation, maybe not dysplasia, but give us a better handle on whether we're really healing mucosa like we think we should. The genetics picture is always fascinating, and I think that the more we can be specific about whether somebody is a Crohn's-like picture versus an ulcerative-like picture is going to help stratify patients and prognosticate them in the future and same with the marker studies.
I think that moving towards once-daily therapy, whether it's oral, whether it's subcutaneous, whether it's periodic intravenous infusions is going to help patients feel better about the burden of their medication consumption rates.
DR. JANE ONKEN: Dr. Isaacs?
DR. KIM ISAACS: I would agree with Susie. I think that the most exciting things that are coming along actually do have to do with colorectal cancer detection and some of the potential narrow beam imaging to do targeted biopsies. I'm very concerned that a lot of our cancer screening, especially as our patients are getting older, having longer disease, we're doing our standard is to do random biopsies through the colon and I think it's random. If we can target our biopsies we may have a better ability to predict who is going to be at risk for colorectal cancer in terms of outcome, as well as the inflammatory.
In terms of new therapies, the once-a-day therapy, that would be so ideal for this patient population. And the biologics are interesting but I would hope that we would get to a point where we don't need the biologics. Genetics is fascinating. Maybe in 10 years we'll be able to replace a gene and people will not have the degree of disability that they currently do.
DR. JANE ONKEN: What about apheresis? Susie, do you have any thoughts on whether that is an option for patients with ulcerative colitis?
DR. SUNANDA KANE: I do. I do think that might be an option and patients are very intrigued by it because it's a procedure rather than a therapy.
And they're very intrigued by it. We have had problems though in our study site with thrombosis and thrombophlebitis. That concerns us and it's been more than one patient who has had very clinically significant thrombotic events after apheresis. So I think that the Japanese who use it quite frequently, their patients are very tolerant and will sit for two to three hours for five to six days in a row. Our American patients won't. So I think it's going to be trying to find the right regimen for them, which is going to be the difficult part.
DR. JANE ONKEN: I agree. I think that Kim's point is right. Once-daily tablets or pills or oral medication is probably the simplest, but I certainly have a patient population that is intrigued, as you say, by the idea of taking poisons out rather than putting poisons in. They don't seem to like to take therapy, oral therapy and they want to minimize their treatment if at all possible. One point you touched on, Kim, was the random biopsies. Historically, we have been taught to take four biopsies, at least four biopsies every 10 centimeters, if not more, for the length of the colon with a minimum of, say, 32 to 36 biopsies. Is that your practice, and do you think that is sufficient?
DR. KIM ISAACS: That is what our current practice is, but we again -- there is one small study that looked at random biopsies and compared this to targeted biopsies using chromoendoscopy and the random biopsy yield was very, very low, where the targeted biopsy yield was higher for dysplastic lesions. So I think that as these technologies become available, and they're here, especially some of the chromoendoscopy methods, the different lights shining on the colon, I think that our practice probably will evolve to only taking targeted biopsies and no random biopsies. But currently without that technology we do four biopsies about every 10 centimeters and making sure that we're getting a minimum of 35 biopsies per patient. The other thing to do is to check with your pathology lab and find out how many they can read per bottle that we submit and try to optimize what you're taking, what you're sampling for your particular lab's needs.
DR. JANE ONKEN: Susie, how do you perform surveillance colonoscopy?
DR. SUNANDA KANE: I do block off actually more time for my surveillance colonoscopies than my standard screening free axis colonoscopies. And I do map four quadrants, 10 centimeters, and I try to get 36 biopsies total. And we have three jars: right colon, left colon and rectum. And so it's usually 15 in the right bottle, 15 biopsies in the left bottle, and then six from the rectum. Then obviously if there is any suspicious looking lesions those go in separate bottles.
DR. JANE ONKEN: You bring up a good point, which is that these procedures do take a significant amount of time. In fact, there was a study not that long ago from Mayo Clinic in which withdrawal time or scope procedure duration was related directly to detection of dysplasia in the ulcerative colitis biopsies. So that the longer a physician took performing the procedure and the implication was this was related to the number of biopsies perhaps that were obtained, the better the detection or the higher finding of dysplasia. And I think it's important for physicians to realize that surveillance colonoscopy can't be added on in a 15 minute procedure slot.
DR. SUNANDA KANE: That's right. And also there is a code modifier, the modifier code 22.-- Where you document that you spent X amount of time, 35 minutes mapping out, you know, 36 biopsies and it's justified if you put it on your report.
DR. JANE ONKEN: Correct. We use that frequently. Well that's all the time we have for discussion on ulcerative colitis. I'd like to thank Drs. Sunanda Kane and Kim Isaacs for sharing their expertise and for their participation in this AGA CME café session. I'm Jane Onken. Thank you for joining us.
