Anti-TNF drugs in ulcerative colitis may not last forever

The duration of benefit of Anti-TNF drugs for ulcerative colitis is not well understood, This article shows about 3 years of benefit on average with some UC patients getting 7 years or more of a response.

When Remicade came out it was a breakthrough in treatment for patients with Crohn’s disease. Eventually it came to be recognized as a treatment for Ulcerative Colitis as well. We went through a time of using it while on mesalamine and azathioprine, then just Remicade alone, now back to with azathioprine at low dose, and perhaps now with mesalamine again.

Aside from how to best administer anti-TNF drugs it was found that patient’s immune systems could make antibodies against them. After all, the drugs like Remicade (infliximab) and Humira (adalimumab) are themselves antibodies and therefor are proteins. The patients’ immune systems see these as foreign proteins and therefor can develop an immune reaction against them. Infliximab and adalimumab were designed to minimize immugenicity. (Immunogenicity is the word that describes no stimulating something is to the immune system). However, the immune system responds very well to foreign substances. An immune reaction often develops.

Inflammatory bowel diseases are also the result of many aspects of the immune system driving a reaction. While Tumor Necrosis Factor is one of the control proteins of the immune system it is not the only one. A patient may have multiple drivers of their disease in addition to TNF. This probably explains why only about half of patients respond to Remicade in the first place.

Once a patient responds and is on infliximab or adalimumab will it work forever? Gastroenterologists find that after a few years patients may stop responding. Tests can be done to see if antibodies are forming or if the concentration of the drug is low. But sometimes the effectiveness of anti-TNF drugs just wanes.

Crohn’s patients have been treated the longest, since the anti-TNF drugs were first used in them. We see very long duration benefits of anti-TNF drugs in many patients with Crohn’s. A number of studies have looked at the time course of response in Crohn’s disease.

Ulcerative colitis has been treated with anti-TNF drugs for a lesser number of years, so there are fewer articles obout the effectiveness of anti-TNF drugs in ulcerative colitis. An article in IBD Journal, Treatment Persistence of Infliximab versus adalimumab in Ulcerative colitis: a 16 year single-center experience[1], addresses the issue.

In this study researchers at the Nancy University Hospital in in Nancy, France reported on the results of treatment of ulcerative colitis patients that had been on long term therapy for at least 6 months. They selected patients who were treated for UC with either infliximab or adalimumab. Patients treated just for pouchitis were not included and neither were patients who had just gotten intermittent doses.

They found 160 UC patients that fit the definition of chronic use of and anti-TNF for over 6 months. In that group 43 patients had started on one of infliximab or adalimumab and swithced to the other. On average, patients responded for about 3 years (3.1 years for infliximab and 2.1 years for adamimumab. Patients that were also on mesalamine drugs had a longer duration of response.

The telling graphic from the study is the analysis of time to failure of anti-TNF treatment, figure 2 in the article.

The label on the vertical axis “Survival Probability” means the proportion of patients for whom the anti-TNF drug continued to work, not time to death. The label could better have been “Proportion of patients still in remissiokn.” The number at the top is 1, meaning 100%.

Looking at the graph everyone was good for a few months, but then the drop-off is evident. While the average time of benefit was about 3 years, that includes the people with long term benefit. So for infliximab about half of individuals lost benefit at 2.3 years, and about 25% of patients had benefit that exceeded 10 years. For adalimumab, about half of individuals lost benefit at 1.7 years, but, similar to infliximab, about 25% had long term benefit.

This sort of data is very helpful in deciding on how to use anti-TNF medications. The study only looks at infliximab and adalimumab. Golimumab, certolizumab were not included, but those drugs are not as commonly used as infliximab and adalimumab in the treatment of UC.

The study is from an academic medical center, where patients are referred from the community, often sicker and less responsive than patients in the community. Thus, results may be worse than seen in community centers.

Reference:
1. Lieven Pouillon, Cédric Baumann, Hélène Rousseau, Myriam Choukour, Charlotte Andrianjafy, Silvio Danese, Laurent Peyrin-Biroulet, Treatment Persistence of Infliximab Versus Adalimumab in Ulcerative Colitis: A 16-Year Single-Center Experience, Inflammatory Bowel Diseases, Volume 25, Issue 5, May 2019, Pages 945–954, https://doi.org/10.1093/ibd/izy322

A review of new drugs for treatment of IBD

Perhaps you’re getting confused by all the medications that are now available for treating IBD. A recent article in IBD discusses the drugs by groups.

Year ago all we had to treat IBD was prednisone. Sulfasalazine ushered in the era of mesalamine drugs. Azathioprine was available as well. Then it got interesting. Our colleagues in immunology research looked into what drove the immune response and identified cachexin, also known as Tumor Necrosis Factor alpha, or TNF-α for short, as a major signaling protein in immune responses. cA2 was an antibody directed against TNF-α, which was shown to be useful in Crohn’s. Soon named Infliximab, the antibody revolutionized treatment of inflammatory bowel disease.

But our immunology colleagues have not been idle. The immune response control system has ben studied for years now, and additional targets ahve been identified in the immune system. We now have more drugs than we could have dreamed of years ago for the treatment of IBD.

A recent review [1] published in IBD Inflammatory Bowel Diseases, a journal of the Crohn’s nd Colitis foundation has provided a nice summary of some current and new drugs for use in IBD. It’s worth a read. I’m providing some highlights here.

First off, the graphic on the cover of IBD is awesome. The immune system is complex, and a cartoon such as was on the cover is very helpful in putting a model in the readers head. I took this diagram off the cover of the issue of IBD. I really like the diagram. You can see that it shows a number of the molecules that are involved in the immune system of IBD.

Anti-adhesion agents

First mentioned in the review are the Anti-adhesion agents. You see, for the immune system to deliver immune cells to that are of inflammation, the cells of the immune system have to migrate to the area on inflammation. I recall stunning videos of immune cells whipping around in the vascular system, with cells stiopping in surreal instantaneity at the place they need to migrate, and then migrate through the wall of the blood vessel to the are of inflammation. If you can stop cells from finding where they need to go, the immune cells will not get to their targets and an inflammatory resposnse can be prevented. Natalizumab was the first drug in category to come to clinical practice. A protein on the surface of immune cels, α4β7/α4β1, binds to a structure named MAdCAM-1 and a structure on the inner surface of blood vessels (VCAM-1 – Vascular Cell Adhesion Molecule-1). Natalizumab is an antobody that binds to α4β7/α4β1, shich bloks cells from binding to blood vessel linings, thus preventing an immune response.

Regretably, natalizumab has been associated with the develoopment of Progressive Multifocal Leucoencephalopathy, a dangerouse disease caused by reactivation of infection by the JC virus, a not uncommon infection that the immune system usually keeps under control.

This is an example of how, even though we have a promising new drug, surprises appear when we block the immune system, allowing an infection that stays controlled by the immune system.

Vedolizumab is another anti adhesion drug. This antobody just blocks the α4β7 protein. Progressive Multifocal Leucoencephalopathy does not seem to occur with this drug. The review nicely describes the studies that support the use of Vedolizumab.

The review describes a drug under study, Etrolizumab, which is directed against the β7 molecule, so it is effective in interfering with several of the proteins that are involved with cell binding to surfaces.

AJM300 is another drug under study, but is special because it is not an antibody. It is a small molecule which blocks immune cell binding to the MAdCAM-1 and VCAM-1 proteins. This is a welcome new agent, as it can be taken as a pill rather than an injection, which is needed by antibodies. Time will tell what adverse reactions happen. Certainly, the incidence of progressive multifocal leucoencephalopathy will need to be watched for, since that problem was seen with natalizumab.

Anti-interleukin Inhibitors

Aside from TNF-α, other immune proteins are involved in the cascade of immune reactions that drive inflammatory bowel disease. IL-2, IL-12, IL-23 are all important. While prednisone blocks IL-2, the drug ustekinumab blocks IL12 and IL-20. It is effective in Crohn’s disease and psoriasis.

Risankizubmab is under development. It looks like it will also be effective in Crohn’s disease.

JAK/STAT inhibitors

In the immune system a number of chemicals are important in regulation of the immune system besides the interleukins. That is because the proteins that regulate the immune system interact with cells which then elaborate internal chemicals in response to stimulation by the interleukins. One such system is the JAK/STAT proteins. If those cellular signalling systems can be blocked then the immune system can be shut down in another way.

Tofacitinib is currently on the market, and works by blocking the JAK system. It works in Psoriasis and Ulcerative Colitis. It is a small molecule, and taken as a pill rather than an injection.

Filgotinib also blocks the JAK system, but works better in Crohn’s disease. It is currently under investigation.

Spingosine-1-phosphate receptor modulators

The review gives short shrift to this class of immun modulators, and honestly, I need to brush up on this system to tell more about what it does in the body. A drug, Ozamimodh is a small moledule orally administered It is in development and is promising for Ulcerative Colitis.

Stem Cell Therapy for perianal Crohn’s Disease

The review describes the injection of stem cells for treatment of perianal fistulas. As the review states, it isn’t known how stem cells work. These are very experimental treatments. The therapy advertised which uses cells from the stems of plants are not stem cells in the sense of stem cells from humans and have nothing to do with this.

Conclusion

This review looks over the new therapies of Anti-adhesion agents, Anti-interleukin Inhibitors, JAK/STAT inhibitors, Spingosine-1-phosphate receptor modulators, and Stem Cell Therapy. While it is written fo rthe professional, a non-professional can glean the complexity of the immune system and the exciting new options for treatment that the future protends. I’d quibble with the term Anti-interleukin Inhibitors since Anti-interleukin antibodies would be a better term. But overall the paper does describe new treatments that are available and others that will be available in the future.

Reference:

1 – A State-of-the-Art Review of New and Emerging Therapies for the Treatment of IBD. Chudy-Onwugaje KO, Christian KE, Farraye FA, Cross RK. Inflamm Bowel Dis. 2019 Apr 11;25(5):820-830.

A lower cost option for prescribing oral vancomycin

I do get irritated by some things I see happening to IBD patients. There is an infectious condition called Clostridium difficile colitis which can be treated with antibiotics. One antibiotic, vancomycin, is very expensive when used in the capsule formulation, but inexpensive when supplied as a solution.

Vancomycin is a treatment for C. Difficile colitis, but can it be obtained for less than $1000?

I had a patient, recently, who is uninsured who was treated for C. difficile colitis. I was saddened to hear that she was given a prescripiton for oral vancomycin capsules. If there is one way to sour a self-pay patient on modern medicine it is to prescribe off patent medications in an expensive formulation. I have to say I learned this trick a long time ago from a coleague. I regret I don’t recall who told me, but it saves thousands of dollars.

Do I exagerate? No! Vancomycin capsules for a 10 day course of 250 mg four times a day cost upwards of $1000? So, how do you save money? Get a pharmacist to dispense the solution used for IV administration.

IV vancomycin has been available for years for about $15 for a 10 gram dose. That is just the amount needed for an oral course of therapy. Just have the pharmacist mix up the following:

Vancomycin HCl 10 g inj.1 vial
Saccharin Sodium0.4 g
Stevia0.4 g
Glycerin80 ml
Raspberry concentrate0.2 ml
Distilled waterqs 200 ml

This has a stability of 14 days if refrigerated. She has Crohn’s disease and has recurrent C. diff which I found upon scoping her, today. This script will cost about $50-$80, saving her about $900 to $1000. She thinks I’m great for having found this cheaper alternative. Next step may be a stool transplant (which might cure her Crohn’s!).

I found this recipe for compounding Vancomycin at the American Society of Health-System Pharmacists web site. The internet is a wonderful place, and Google serves us well. The recent script I wrote left out the Stevia, and just ordered “flavor, prn”, leaving that to the judgement of the pharmacist. Don’t fear writing a compounding prescription. Pharmacists are our friends, and they like the chance to provide this service to our patients.

Patients Can Have Feelings of Loss When IBD Improves

Patients will often improve. Yes, really, it does happen! It is interesting that getting better can be a type of loss. The patient improves, then loses their routine, and the physician loses a patient with which he was having regular followup. I relate an episode of arecent loss such as this.

The following is a post that was in the IBDList. Tom, the list moderator, added the comment at the end set off by brackets. The IBDList is a very valuable Maillist server for people interested in Crohn’s and colitis.If you like the sort of stuff you see here you would like to get the IBDList.

I had an interesting emotional response recently with a patient who was put into remission by surgery. This woman had her first attack of Crohn’s about a year ago. She did well with steroids, almost came off prednisone after a slow taper, then went back on with a flare. On attempting to re-taper she had another flare that turned into abscess. Surgery was required. TheCrohn’s diseased tissue was very thickened, and perhaps it would never have healed with medical treatment.

I had seen her about once ever month or every other month during this time and I got to know her well. When she came in for the post op check-up she was off all her medications and doing very well, eating anything she wanted, all the visible steroid effects gone. While I should have been happy that she would not have to see me anymore, I found myself somewhat sad. It was feeling the feeling of loss.

Clearly what was happening was that the patient and I had been having success at dealing with the Crohn’s, and much of the satisfaction for me was the continued followup and advice that kept her going and the improvement she had following my advice. Knowing that I would not have to do that any longer was, I think, the basis for this. I think another aspect was that she came to surgery without my having given the advice. Having a patient go sour is disconcerting to the physician (certainly more so to the patient),but there is something of a feeling of “how dare that Crohn’s disease get worse just as I was dealing with it.” Part of GI training is to have the knowledge that surgery is not an evil to be avoided, but rather a tool to be used as needed.

I recall a post Tom put up on the IBDList a while back about having a feeling of loss when in remission from IBD. The loss was in not doing the dietary restrictions and other things that had become routine, or familiar, to daily life.

Oh, the reason I put this up is that this is a list about IBD, living with it, and treatment of it. While I don’t think there is anything in this post that will affect what anybody does, it is the case that IBD affects many people besides the patient, and the physician is one of them.

Stephen Holland, M.D.

[ Thanks for an interesting perspective. I know that when a GI I had been seeing for a number of years retired, I missed him as a person as much as missing the physician. I never considered that he also might have feelings of the loss of day-to-day contact with his set of patients.

Diabetics these days often have a team of professionals helping them with their disease since it affects so many areas of physical, emotional and spiritual life. In a way it is too bad that the medical community often doesn’t take a more all-encompassing approach to diseases such as IBD that are influenced by more than just the steroids or sulfa drugs. Maybe one day the insurance companies will realize that a combination of treatments, along with a healthy look at eastern or alternative medications and procedure scan actually be cheaper than the most common methods of symptom-treatmen tor emergency-care medicine. -tom]

Probiotic Studied in Pouchitis

Probiotic is a term that refers to good bacteria that are given to fight disease. Whatever the merits of the term probiotic, we finally have a study that was well done. The study publishedin the journal Gastroenterology was very clear: in a group of patients with the problem of pouchitis there was clear benefit.

I think those are excellent examples of what probiotics have the potential to do. I agree, the data on C. diff colitis looks most compelling to date. The editorial in Gastro this month was prompted by a study that was in the same issue, relating to the use of probiotics in pouchitis, the problem of inflammation in the small intestinal pouch created during ileoanal anastamosis after removal of the colon for ulcerative colitis. To put the horse before the cart, review of the article (by Gionchetti et. al. Oral Bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial) would seem in order.

The study looked at 40 patients with pouchitis all of whom were in remission on drugs. The drugs were then stopped and the 40 patients were then either treated with placebo (maize starch) or a bacterial product called VSL#3 taken twice a day continuously. The trial followed these patients for up to 9 months. In the placebo treated group patients started having relapses after a month, and then all 20 patients eventually relapsed over the next three months, about 2 relapsing each week. In the VSL#3 arm of the study 3 of the 40 patients had relapse over 9 months. Bacteriological evaluation showed that the germs in the stool changed over time with more bifidobacteria, lactobacilli, and strep. salivarius present. The did not subspeciate the bifidobacteria or lactobacilli, however. 

This is the first paper I have seen on bacterial supplementation which is randomized and controlled. As such, it porvides usable data upon which to make medical recommendations. The product used in this trial was shown to provide protection from relapse in the subgroup of patients with pouchitis in the setting of ileoanal anastamosis with chronic pouchitis who had been well controlled on drugs. 85% of patients had a prolonged benefit, compared to 0% on placebo. 

This study provides useful information because it is a controlled study, the patient groups are well described, and sufficient detail is provided to understand the expected benefits of the treatment. The study applies to those with pouchitis who were in remission on medications who took VSL#3. It shows that the bacterial treatment is almost as good as antibiotic treatment for maintenance of remission of pouchitis. (15% failure rate for bacteria versus 5% for antibiotics) The control group was interesting. Maize starch may not have been the best choice of starch. Maize contains certain types of starches that are not digestible by amylase. This means that patients on Maize starch will deliver carbohydrates to the lower intestine, or to the pouch in this case, which could potentially aggravate the pouchitis. Had they used rice starch this would not have been the case. However, the patients selected for the study were patients who were having a lot of relapses anyway.

VSL#3 is an unusual probiotic. It is comprised of 8 different bacteria. Also, they are at very high concentrations and have been freeze-dried. In animal and in-vitro studies single strain mixtures are not able to effectivly change the flora already present in the gut. Also, old studies of germ free animals show that putting in a single germ is generally lethal, but that a mixture of germs is beneficial. These results were the basis for formulating a mixed bacteria supplement. 

These issues raise doubts as to whether single strain bacteria would be as effective as multi strain mixtures. Two studies in ulcerative colitis in the past have shown no benefit with a single strain, but an open label trial suggests there may be some benefit to VSL#3 in UC.

Bacteria are very different from one another, and the diseases Crohn’s, UC, pouchitis, and c. difficile colitis are very different as well. While this mixture now has been shown to work in pouchitis much more needs to be done to determine how well other probiotics work in this and other diseases.

Sartor’s editorial was interesting. After reviewing the study he discussed other studies of probiotics. A strain of E. coli has been shown to have the effectivness of low dose masalamine in maintaining remission in UC. However, there are very few studies of benefits of probiotics. Whether all the strains that were used in this study are needed is not known, and whether other probiotics will help better is not known. Other approaches such as altering the carbohydrates delivered to the gut need to be studied. Sartor also reviewed proposed mechanisms – suppression of resident bacteria, stimulation of gut mucus, prevention of adherence of bad germs, and induction of gut immunity ( including affecting the type of immune response generated ). 

While the editorial was interesting, it did not give blanket support to the use of probiotics. It called for a carefull set of studies so we can understand what probiotics can and cannot do, and emphasized the fact that not all bacterial products are the same. 

If I had pouchitis that had previously responded to treatment I would consider the probiotic if I was one of those few patients with multiple relapses of pouchitis. However, I would expect to need to get the product from overseas and I would then need to take it twice a day forever. This in comparison to taking a course of antibiotics for 10 days three times a year. 

The interesting question is what to do if you are one of the patients that never responded to treatment. Potentially you immune response is different or your flora is different. Whether you would respond to VSL#3 is not known. It would be worth trying, but I would recommend a trial were done under medical supervision in case being such a special patient put you at risk for a flare or other complication when taking that mixture.

The study looked at 40 patients with pouchitis all of whom were in remission on drugs. The drugs were then stopped and the 40 patients were then either treated with placebo (maize starch) or a bacterial product called VSL#3 taken twice a day continuously. The trial followed these patients for up to 9 months. In the placebo treated group patients started having relapses after a month, and then all 20 patients eventually relapsed over the next three months, about 2 relapsing each week. In the VSL#3 arm of the study 3 of the 40 patients had relapse over 9 months. Bacteriological evaluation showed that the germs in the stool changed over time with more bifidobacteria, lactobacilli, and strep. salivarius present. The did not subspeciate the bifidobacteria or lactobacilli, however. 

It is possible for a physician to have feelings of loss when a patient improves

It is possible for a physician to have feelings of loss when patients improve.

The following is a post that was in the IBDList. Tom, the list moderator, added the comment at the end set off by brackets. The IBDList is a very valuable Maillist server for people interested in Crohn’s and colitis. If you like the sort of stuff you see here you would like to get the IBDList.

[Unfortunately, the IBDList stopped publishing a number of years ago – Ed.]

I had an interesting emotional response recently with a patient who was put into remission by surgery. This woman had her first attack of Crohn’sabout a year ago. She did well with steroids, almost came off prednisone after a slow taper, then went back on with a flare. On attempting to retaper she had another flare that turned into abscess. Surgery was required. The Crohn’s diseased tissue was very thickened, and perhaps it would neverhave healed with medical treatment.

I had seen her about once ever month or every other month during this time and I got to know her well. When she came in for the post op checkup she was off all her medications and doing very well, eating anything she wanted, all the visible steroid effects gone. While I should have been happy that she would not have to see me anymore, I found myself somewhat sad. It was feeling the feeling of loss.

Clearly what was happening was that the patient and I had been having success at dealing with the Crohn’s, and much of the satisfaction for me was the continued followup and advice that kept her going and the improvement she had following my advice. Knowing that I would not have to do that any longer was, I think, the basis for this. I think another aspect was that she came to surgery without my having given the advice. Having a patient go sour is disconcerting to the physician (certainly more so to the patient), but there is something of a feeling of “how dare that Crohn’s disease get worse just as I was dealing with it.” Part of GI training is to have the knowledge that surgery is not an evil to be avoided, but rather a tool to be used as needed.

I recall a post Tom put up on the IBDList a while back about havinga feeling of loss when in remission from IBD. The loss was in not doing the dietary restrictions and other things that had become routine, or familiar,to daily life.

Oh, the reason I put this up is that this is a list about IBD, living with it, and treatment of it. While I don’t think there is anything in this post that will affect what anybody does, it is the case that IBD affects many people besides the patient, and the physician is one of them.

Stephen Holland, M.D.

[ Thanks for an interesting perspective. I know that when a GI I had been seeing for a number of years retired, I missed him as a person as much as missing the physician. I never considered that he also might have feelings of the loss of day-to-day contact with his set of patients.

Diabetics these days often have a team of professionals helping themwith their disease since it affects so many areas of physical, emotional and spiritual life. In a way it is too bad that the medical community often doesn’t take a more all-encompasing approach to diseases such as IBD that are influenced by more than just the steriods or sulfa drugs. Maybe one day the insurance companies will realize that a combination of treatments, along with a healthy look at eastern or alternative medications and procedures can actually be cheaper than the most common methods of symptom-treatment or emergency-care medicine. -tom]

_________________________

Update: 7/1/2019

I wrote this years ago. Now, about 20 years later, this feeling of loss doesn’t happen. But now patients are on immunosuppression, surgical procedures are followed by continued follow up for regular follow up. We realize there are so many things we do and look out for in our IBD patients that we don’t have patients that don’t need to see us after surgery. We continue to see our patients to keep recurrence rates low. It’s a different time now, with continued improvements in the outcomes of our patients with IBD

– SPH

What to Do When You Feel Like Your Problem is a Burden to Others

Do you feel like a burden to your physician? Other patients do too. My feeling on the matter.

A reader of the IBDList wrote:

So much about having these illnesses cannot be communicated to your own physician in a 15 minute or even a 2 hour appointment. I have an excellent gastroenterologist, but he is extrememly busy and, unless I am in extreme distress at the time, I always hesitate to take up his time. And, of course, some of it just isn’t discussed because it is part of the illness. How do you convey pain? Or extreme embarrassment?

That’s why the list is so important. Sometimes, you just feel likethere is no one to tell or understand. Family members and friends can try to understand (or not), but this goes on so long and is so personal thatyou begin to feel that you are just making people feel worse, so you stoptelling anyone.

When I see comments such as this I have mixed feelings. I want patients to be able to express themselves and talk about their problems. However,I understand that as much as one may try to understand a patients condition,there is a world of difference in understanding the condition and actuallyhave suffered the illness. The physicians role is to understand the patient,the disease, and the treatments well enough to give good advice. Thus,the patient may give enough information to allow the physician to givegood advice, but that may well not be enough for the patient in terms ofemotional support.

Since physicians are limited to understanding the disease through theirpatients, I think it is important for patients with chronic diseases toseek out support groups. Sharing one’s problems with someone who has beenthere is important. Unless your doc has IBD, you probably cannot get thatlevel of understanding. Perhaps, even if you have a doc who has IBD, itis still not the same, for docs know the disease well enough that thereis perhaps less fear of the unknown, even if it is a happy little delusion.

That said, lets use some common sense as well. If you ahve a doc whonever has the time, it may be time to help that physician by decreasingtheir workload. Another doc who has the time may be what you need. Oneof the marvelous things about medicine is the variety of people you meet- both physicians and patients. The variety of needs that patients haveusually can be met by some physician out there. Another use of supportgroups, getting insight on what each doc in the community is like. 

So, if you feel you are a burdeon to your doc, it may be that you need a new doc. But if it is a matter of not being able to really communicate your burdeons, a support group might be very important for you to join. An online forum of support that I recommend is the IBDList. [The IBDList was a mail-list that was discontinued years ago. The reader is encouraged to browse the internet for on e of the many resources now available, and especially to look the the CCFA for local support groups – Ed.]

Stephen Holland, M.D.
Section of Clinical Pharmacology
University of Illinois College of Medicine at Peoria

Celebrex for the treatment of Ulcerative Colitis – Not a good idea

There is a new antinflammatory drug out on the market named Celebrex. It has less side effects on the GI tract than typical arthritis drugs. Is it possible that it is safe in Crohn’s or Ulcerative Colitis? Well,no. See why in this article.

A reader of the IBDList asked recently if a new anti-inflammatory, Celebrex, would be useful in the treatment of Ulcerative Colitis.  The analogy of sulfasalazine, another drug with a salicylate component was offered as a rational to try it.

Crohn’s and UC are different from arthritis.  Some experience from the past is interesting in this regard.  A chemical in the body called arachidonic acid is converted by a series of enzymes into several chemicals that are part of the signaling system for inflammation. Two class of chemicals, prostaglandins and another, leukotrienes, are of particular interest inIBD.  It turns out that prostaglandins are blocked by drugs like aspirin,Motrin, Nuprin, and other similar drugs.  However, the mesalamine drugs (sulfasalazine, Pentasa, and others) block leukotrienes.

Clinical experience has shown that Motrin and its cousins can actually make UC and Crohn’s worse and cause flares, while mesalamine is beneficial. This clinical observation shows that leukotrienes are an important cause of inflammation in IBD, and prostaglandins are protective.

A new development in arthritis research is that prostaglandins are made by two enzymes, cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2). It has been found that prostaglandins made by COX-1 protect the stomach from injury, while COX-2 products are important in arthritis inflammation. A new drug on the market, Celebrex, (a.k.a. celecoxib) blocks COX-2 but not COX-1.  It was predicted that this drug would be effective in arthritis and cause less injury to the stomach.  Animal studies and human studies have borne this out.

The natural question for IBD researchers – could a COX-2 inhibitor be beneficial in IBD.

To evaluate that question and not put patients at risk, Brian Reuter at the University of Calgary in Alberta, Canada, gave the drug L745337( a drug similar to celecoxib ) to rats which had colitis induced by an enema of TNBS.  (This is a standard animal model of colitis). The results of the experiment were that the colitis was much worse in the rats given the COX-2 inhibitor.  In fact, it was even worse than giving Naprosyn to the rats, which was also done in the experiment.  Additionally, giving etodolac, an NSAID which turns out to be somewhat more specific for COX-2 than the run of the mill NSAID, was almost as bad as the pure COX-2 inhibitor L745337.

These results lead me to recommend against giving Celebrex to anyone with IBD.  It is interesting that the more selective the drug was for COX-2, the worse the rats did.  Certainly, there are other models of IBD, and it is possible that human UC or Crohn’s will act differently at times than the animal models. However, I’d much rather see the animal studies before trying the drug in people.  This is also a good exampleof how animal studies are beneficial.

Heparin for the Treatment of Refractory Ulcerative Colitis: Results of a Controlled Trial

A trial of heparin in ulcerative colitis has been completed. Read about the results . (I am proud to have participated in that trial.) I previously wrote about findings at previous DDW meetings. Here is an overview and several abstracts about heparin in IBD that provide background information: Heparin in UC or Crohn’s?

I have reported previously on the use of heparin in Ulcerative Colitis.  A trial of heparin versus placebo wasrecently done.  The study was organized by Dr. Korzenik, now at WashingtonUniversity School of Medicine in St. Louis, MO.  I ran one of thesites that participated in the study.  The results of the study wereeagerly awaited.  The results of the trial were recently reportedat a session of Digestive Disease Week, a major international meeting thatI attended in Orlando, Florida.  Following is the abstract as published,with notes afterwards that I added.  The short answer is that it works. Read on for details.
 

Korzenik J, Bitton A, Robert M, et al.A multi-center, randomized, controlled trial of heparin for the treatment of ulcerative colitisGastroenterology 1999, 116:A752.

Background: A series of open-labeled trials suggest a benefit of heparinfor the treatment of Inflammatory Bowel Disease (IBD). No prospective randomizedcontrolled trials have been performed. We report the initial data obtainedfrom a large multicenter controlled trial of heparin therapy for the treatmentof moderate to sever ulcerative colitis (UC). Aims: To assess safety andefficacy of heparin in the treatment of active UC. Methods: Subjects wereenrolled with moderate to severe ulcerative colitis having four or morestools/day. Permissible concomitant medications included mesalamine, steroidsand azathioprine/6-MP for specified durations prior to enrollment. Subjectswere randomized (1:1) to saline injections or standard porcine heparininjections at 10,000 units subcutaneously (sq) bid for 6 weeks. In thoserandomized to heparin, the dose was adjusted by an unblinded observer to10,000 units sq tid for patients whose appt remained below the upper limitof normal. A subgroup (20%) of subjects randomized to placebo receivedtid saline injections. Randomization was stratified by extent of colitis(left sided vs pan – colitis) and by use of steroids. Patients were monitoredwith weekly aPTT and twice weekly CBC. Efficacy was determined by clinicalassessment of stool frequency, frequency of bloody stools, patient globalscale, physician global scale, sigmoidoscopic and histologic assessment(at week 0 and end of week 6). Failure was established by an increase inexisting medications or need for additional medication. Decrease of hematocritby 6 points or decrease of platelets below 100,000 was also criteria fordiscontinuation. Results: 70 subjects were enrolled at 9 sites. No severe adverse effects were observed in any subject. One subject was prematurely discontinued because of a decrease in hct of > 6 points but was in remissionat the time with no evidence of bleeding. Three patients noted a transient increase in rectal bleeding though not clinically significant and wereable to continue their involvement. One patient developed a psoriasiformrash at the injection sites. Enrollment has been completed, but the trialhas not yet been unblinded. Conclusions: 1) The use of heparin is safein the setting of moderate to severe ulcerative colitis. 2) Several subjects are completing their involvement at this time. Data for clinical efficacy will be reported after the trial is unblinded and will be available shortly.


At the conference the results were further detailed.  The majorresult was that the remission rate was 42% for patients on heparin, 20%for control patients.  It should be noted that these patients wereall not responding to regular therapy, so heparin was started only latein the course of their UC flare.  There was no significant increasein bleeding rates.  Patients that did respond all started to respondby three weeks.  One issue that was discussed was that the heparinwas given subcutaneously rather than intravaneously.  This was done because it was an outpatient study.  Since heparin given subcutaneouslymay make different fractions of the heparin available differentially, itis possible that IV use is more effective.  Note, also, the placeboresponse rate.  20% is somewhat low for a placebo response rate, showingthat these were chronically ill patients.  Nonetheless, 20% of patientsdid go into remission with just another month of their treatment withoutheparin.  This shows the importance of a placebo controlled trial. Had the control group not been included a result of just 40% response mighthave been believed to be placebo alone.  The placebo group shows that the response was real.

The information here is from an oral presentation.  These results have not been published in a journal and have not been carefully reviewed by outside experts.  A number of the results described in preliminary form do not turn out to be true.  The usefullness of a preliminary report is for early distribution of results and for feedback to the author before publication.  Due care needs to be exercised when acting onpreliminary results.

Concerns Regarding the Use of Nonprescription Drugs in Crohn’s and UC

The nature of Crohn’s and Colitis is not known. I think this is one cause of patients using nonprescription drugs, often misnamed nutritional supplements. A reader of the IBDList asked my opinion of Salmon Oil after reading the article on this page regarding Purepa. My reply was really a discussionof these unregulated drugs, Concerns Regarding the Use of Nonprescription Drugs in Crohn’s and UC.

A reader asked:

Dear Dr. Holland:

As the mother of a 22-year old son with Crohn’s, I have valued your input on the IBDList for the past year. Today was my first visit to your IBD page.

In addition to being on Asacol, I have had my son on a variety of other natural “remedies” including cat’s claw, aloe vera capsules, vitamins and salmon oil.  After reading your article about Purepa, I am anxious for him to give it a try.  Do you feel this would have a greater benefit than the salmon oil capsules?  If so, do you know if it is yet available in the U.S. (the article you referred to was published in 1996).

Thank you in advance for this information. I appreciate everything you do to further the quest for a cure for Crohn’sand UC.

P.S.  My son is currently a patient at the Univ. of Iowa Hospitals (Center for Digestive Diseases). Do you feel they have an adequate “handle” on IBD? Are you taking new patients?


U of Iowa is well respected.  An important question in getting a handle on the case is to be sure they know your son is on a number of non-prescribed medications.  There is a misconception that many share that natural remedies are not medications.  Consider this:  A drug is a substance which is taken to affect a patient’s metabolism in some desireable way.  These natural products really are being used as medications by many.  The trouble doctors have in dealing with them is that there is in general no safety or efficacy data available to base any recommendation upon.  The drug companies that sell these materials have lobbied congress and have gotten laws passed that have prohibited regulation of themselves.  They also have a fig leaf of a regulation that says as long as they just say the magic words “nutritional supplement”they can market to the public without any regulatory oversight.

There is another misconception that natural substances are safe. There are tragedies in the medical literature of liver failure causing death in several children due to daily administration of certain herbal teas.  The teas were known to be hepatotoxic, but the labelling didnot include this (didn’t have to, it was a nutritional supplement). There are a number of natural substances that are known to be toxic insufficient doses.  Nicotine, caffeine, digitalis, aspirin, strychnine,castor oil, ipecac, poppy juice, to name a few.  (The last exampleis particularly instructive. Poppies are a source of opiates which causedwell documented toxicity to Dorothy, Toto, and the Cowardly Lion. The Tin Man and Scarecrow were spared, due to a difference in metabolism.) There are cases of death due to contaminated tryptophan.  Just because something comes in pill form does not mean it is as safe as people have come to expect from pills from regulated drug companies.

You may be aware that the risk of drug interactions goes up with thenumber of drugs taken.  With your son being on four different additionalmedications than prescribed there is the potential of drug interactions.

So, what are the drugs you are giving your child doing?  I don’tknow.  Indeed, I know that no one can know.  The products describedare all complex.  Aside from the vitamins, their manufacture is notregulated.  Fish oils can be a source of dioxins.  I wonder ifany of the nonprescription drugs your son is on have been through any regularmonitoring of known or likely contaminants.  The medical literaturealso contains articles showing that the unregulated drugs are sometimesmisidentified by the manufacturer.

I try to limit my advice to matters for which there is some sort ofexperience with the substance at hand which can predict how a patient willdo.  The need for the evidence to be predictive is what patients reallywant.  It is expected that a doctor could explain what the expectedeffect would be, what the side effects would be, and the chance of eitherhappening.  For the majority of unregulated drugs, the evidence forthe medicines marketed as nutritional supplements is anecdotal, which doesnot help one make predictions as to how a patient will respond.

All that said, what can I say about your particular questions?  Well, I do not have data on efficacy or side effects of Salmon oil in Crohn’s. Thus, prediction of relative effects is not possible.  (I even donot know if Purepa is whole fish extract or part fish extract.  Asa licensed drug, processing must adhere to Italian good manufacturing practicesand will therefore be consistent lot to lot.)  I also do not knowwhat interactions would develop, if any, with the other medications heis on.  As to Purepa, note that the patients in the study were selectedwith criteria that predicted a high chance of relapse.  The singlestudy thus applies to patients with the same clinical features.  Itis probably generalizable to patients outside Italy, though the fact thatItalians eat more olive oil is one reason that studies in other countrieswould be good.  Whether the drug would be beneficial to patients witha lower risk of relapse is not known.

The simple answer, therefore, is “I do not know.”  The reason forwriting all of the above is to explain the underlying concerns that I asa physician have that causes me to say “I do not know”.  As a fellowprescriber of medications I urge you to consider the risks and benefitsof your recommendations.  Also, I hope that you are keeping recordsof clinical response and medications (including dose and regimen and lot/batchnumber).  These records would be valuable for determining likely candidatemedications relating to clinical response, good or bad.

I hope for the best in your son’s case.