Dear Doctor is a regular feature in The Journal. Questions are answered by Dr. Remo Panaccione. The following questions are excerpts from The Journal. If you have questions concerning IBD, please forward your inquiries to publications@ccfc.ca or mail your letter to:
Dear Doctor, CCFC Journal
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Dear Doctor
Q: I was diagnosed with ulcerative colitis, but the doctors were constantly thinking I also had Crohn’s. When I had my ileostomy surgery in 1998, it was found that I had what they called Crohn’s-colitis. Now 12 years later, I am having severe abdominal pains and other signs of a recurrence. Is it possible with a diagnosis of Crohn’s-colitis to have a recurrence anywhere else in the digestive tract after an ileostomy?
A: As you know Crohn’s disease (CD) and ulcerative colitis (UC) are related chronic inflammatory disorders of the intestine. CD can affect the entire GI tract from “gum to bum,” whereas UC is isolated to the large intestine or colon. When IBD affects only the colon, it can be either Crohn’s-colitis or UC. Sometimes it is difficult to distinguish the two and it is termed inflammatory bowel disease undetermined type (IBDU - what we once called indeterminate colitis).
There are several points that are relative to your question. If the thought was that you had Crohn’s-colitis at your surgery, there is a 10 to 15 per cent chance that over time, it could show up in your small bowel or elsewhere. A colectomy with an ileostomy is a good surgery, but it is not an absolute cure in Crohn’s-colitis. Most patients will not have a recurrence in the small intestine because the location in CD is usually static, but as mentioned, 10 to 15 per cent will.
Similarly, two to five per cent of patients with ulcerative colitis may end up developing CD after a “curative” surgery. Whether this represents a misdiagnosis, a situation where the patient had UC and developed CD or the diseases in fact co-exist is difficult to determine.
If you are having symptoms, you should definitely be reassessed to ensure you do not have CD of the small intestine or the upper GI tract.
Q: I was diagnosed with ulcerative colitis two years ago and have been fortunate that I’ve only had to take three Asacol tablets a day. I had what I understand is called a flare-up a few months ago. I had my dosage increased to two pills three times a day, but there has been no change. I was then put on Salofalk (2 mg) and cortifoam. This helped my symptoms.
I just finished the cortifoam and am still taking the Salofalk. I’ve only been able to deal with my specialist over the phone, but he’d like me to continue taking the Salofalk until I see him (four months from now). Is this not a long time to be taking it? How long is a ‘flare-up’ and what should one be expecting during this time?
A: Therapy for mild to moderate ulcerative colitis consists of oral mesalamine (brand names include Asacol, Salofalk, Pentasa, Mezavant, Novo-5-ASA) alone or in combination with topical mesalamine (suppositories or enemas) and sometimes topical steroids (cortifoam, cortenema, entocort enemas). These drugs are used for induction of remission and maintenance of remission. Oral doses range from two to 4.8 grams per day. Some patients will require higher doses.
However, at higher doses it is expected that patients will achieve remission in the induction phase after four-to-six weeks (hopefully sooner). If a patient does not achieve remission by this time, other strategies to induce remission should be explored. This could include adding topical medications, if not already used, or considering a course of steroids.
The important thing to remember is once you achieve remission, you need to maintain it. This usually means life-long prolonged therapy with mesalamine. The mistake most patients make is that when they feel better they reduce or stop taking their medication. This invariably will lead to another flare over time. Unfortunately, chronic diseases such as ulcerative colitis require chronic therapy. Fortunately, mesalamine products have a large therapeutic window, meaning they are considered extremely safe even over the long-term, with side effects being rare.
Q: I recently underwent a routine upper GI and scope as part of my new specialist’s process. The upper GI revealed a large mass that, upon further CT examination, determined me to be in serious active flare (43 cm +). However, I’m exhibiting no visible symptoms. Have you encountered this? I need to work with my specialist on treatment, but am puzzled at the lack of symptoms.
A: It is difficult to comment specifically on the mass and what this represents. However, it is not uncommon for patients to have active disease in the absence of symptoms in Crohn’s disease. It has long been known that there is a disconnect between patients’ symptoms and disease activity. The lack of this realization often leads patients to have periods of significant disease activity (inflammation) without symptoms, which then leads to complications such as fibrostenosis (obstruction), fistulas, or abscesses. That is why it is important for GIs to follow patients even when they are without symptoms with markers of disease activity, so that the disease is caught and treated before complications can develop.
This is an area of intense study because it is such a huge problem. Researchers are trying to determine the best way to follow disease activity in the absence of symptoms. Scheduling routine visits with your GP or GI specialist is a start, as is routine blood work looking for markers of inflammation.
Q: I have a friend who has been diagnosed with Crohn’s. She has iron deficiency anemia symptoms, very low iron. She has received three iron transfusions but her iron is still low. Is this common?
A: Iron deficiency anemia is common in patients with Crohn’s disease. In general, iron deficiency is due to poor oral iron intake, malabsorption, (not usually the case in CD), or chronic blood loss (GI tract, menstrual losses, urinary tract, regular blood donation). The first step even in the CD patient is to consider these three large areas. Is the patient taking in enough iron? Is there a reason for the patient to be malabsorbing iron (the most common cause is celiac disease)? Are there other causes of blood loss? If the patient is taking in adequate amounts of iron, has no reason to malabsorb iron and has no other reason for chronic blood loss, then the iron deficiency may be a marker of poorly-controlled disease. The status of the disease should be re-evaluated to ensure there is no active disease or complication leading to the iron deficiency. Other contributing causes to the anemia, such as B12 deficiency and possible drug causes, should also be explored.
Q: I am interested in participating in a study on low-dose naltrexone and Crohn’s disease. I have been unable to find any studies I could join in Canada and was hoping you might know of one.
A: Thank you for your question. Presently there are no studies in Canada regarding low-dose naltrexone. Low-dose naltrexone (LDN), where naltrexone is used in doses approximately one-tenth those used for drug/alcohol rehabilitation purposes, is being used as an "off-label" treatment for certain immunologically-related disorders. The use of LDN for such diseases as cancer was first proposed by Ian Zagon, PhD, and LDN’s broader clinical effects in humans were proposed by Bernard Bihari,MD.
LDN has been used in a variety of conditions including multiple sclerosis (MS), cancer, and fibromyalgia. The results of a pilot study at Pennsylvania State University College of Medicine were reported to an international gastroenterology conference in Los Angeles in May 2006.The trial examined the safety and efficacy of LDN in a group of patients with Crohn’s disease. Dr. Jill Smith, Professor of Gastroenterology at Pennsylvania State University’s College of Medicine concluded that "LDN therapy appears effective and safe in subjects with active Crohn’s disease." Smith and her colleagues have since received a National Institutes of Health grant and are proceeding with a definitive Phase II placebo controlled study. It should be noted that the initial trial was in a small group of patients and was not a standard trial with standard acceptable outcomes. It’s been almost two years since the formal Phase II trial began and the results are still not known. Recruitment has been slow.
At the present time, there is no conclusive evidence for the use of LDN in Crohn’s disease.The preliminary results indicate it may improve some symptoms, but it does not meet any standards as defined by global regulatory authorities. In addition, the use of LDN in Crohn’s disease and other diseases has been sensationalized on the Internet and in reports of the lay press without meeting proper scientific standards.
Q: Quite a while back, I read that there would be three or four new drugs on the market within the next five years for Crohn’s and colitis. Unfortunately, I can’t remember where I read about this; it was either in The Journal or an Alberta Chapter newsletter. I would love to have more info about these up-and-coming drugs and whether or not I would be able to take part in future trials.
A: This is a great follow-up to the previous question. Several years ago, most experts in the field believed that there would be three to four new drugs available on the market to treat Crohn’s disease.This was based on promising results in Phase I/II clinical trials. Unfortunately,most of these agents have failed in the Phase III (pre-approval) studies, demonstrating a lack of efficacy in large trials. Drug development is a complex and long process.
Phase I trials are the first stage of testing in human subjects. Normally, a small (20 – 100) group of healthy volunteers will be selected.This phase includes trials designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a drug. (Pharmacodynamics is often summarized as the study of what a drug does to the body,whereas pharmacokinetics is the study of what the body does to a drug.)These trials are often conducted in an inpatient clinic, where the subject can be observed by full-time staff. Phase I trials also normally include dose-ranging (also called dose escalation) studies so that the appropriate dose for therapeutic use can be found.
There are different kinds of Phase I trials. Once the initial safety of the study drug has been confirmed in Phase I trials, Phase II trials are performed on larger groups (20 - 300) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients.When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to workas planned, or to have toxic effects.
Phase II studies are sometimes divided into Phase IIA and Phase IIB.
- Phase IIA is specifically designed to assess dosing requirements (how much drug should be given).
- Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)).
Phase III studies are randomized controlled multi-centre trials on large patient groups (300 – 3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current ‘gold standard’ treatment. Because of their size and comparatively long duration, Phase III trials are the most expensive, timeconsuming and difficult trials to design and run - especially in therapies for chronic medical conditions.
It is common practice for certain Phase III trials to continue while the regulatory submission is pending at the appropriate regulatory agency.This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at “label expansion” (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), to obtain additional safety data, or to support marketing claims for the drug.
While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug’s safety and efficacy, in order to obtain approval from the appropriate regulatory agencies such as Health Canada, the Food and Drug Administration in the United States, or the European Medicines Agency in the European Union. If anyone is interested in participating in clinical trials, trials in Canada can be found at http://clinicaltrials.gov.
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