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New Insights into the Diagnosis and Treatment of Refractory IBD
Dr. David George Binion discusses the approach to the very sick patient with inflammatory bowel disease.
Upon completion of this activity, participants should be able to:
- Discuss the implications of Clostridium difficile as the most common infectious complication contributing to severe and refractory IBD
- Discuss remission for Crohn’s disease patients with either azathioprine or infliximab monotherapy
- Describe how severe and refractory IBD can be linked to infectious complications (C difficile, CMV), iatrogenic drug reactions, congenital immunodeficiency including hypogammaglobulinemia, comorbidities with depression and chronic pain, and unrecognized stenosis requiring surgery
- Excess hospitalisation burden associated with Clostridium difficile in patients with inflammatory bowel disease. Ananthakrishnan AN, McGinley EL, Binion DG. Gut. 2008 Feb;57(2):205-10. Epub 2007 Sep 28. PMID:17905821
- Infliximab, azathioprine, or combination therapy for Crohn's disease. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, Lichtiger S, D'Haens G, Diamond RH, Broussard DL, Tang KL, van der Woude CJ, Rutgeerts P; SONIC Study Group. N Engl J Med. 2010 Apr 15;362(15):1383-95. PMID:20393175
- Narcotic use in patients with Crohn's disease. Cross RK, Wilson KT, Binion DG. Am J Gastroenterol. 2005 Oct;100(10):2225-9. PMID:16181373
- Cytomegalovirus infection in patients with inflammatory bowel disease. Original Contribution American Journal of Gastroenterology (1999) 94, 1053–1056; doi:10.1111/j.1572-0241.1999.01013.x
- Cytomegalovirus infection in patients with inflammatory bowel disease. Vega R, Bertrán X, Menacho M, Domènech E, Moreno de Vega V, Hombrados M, Cabré E, Ojanguren I, Gassull MA. Am J Gastroenterol. 1999; 94, 1053–1056.
- Increased rates of early adverse reaction to azathioprine in patients with Crohn's disease compared to autoimmune hepatitis: a tertiary referral center experience. Bajaj JS, Saeian K, Varma RR, Franco J, Knox JF, Podoll J, Emmons J, Levy M, Binion DG. Am J Gastroenterol. 2005 May;100(5):1121-5. PMID:15842588
Dr. Binion has financial interests with the following proprietary entity or entities producing health care goods or services as indicated below:
- Grant/Research Support: Janssen
- Consultant: Cubist, Takeda, UCB Pharma, Janssen
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Release Date: 11/30/2012 | Last Modified On: 5/6/2014 | Expires: 5/6/2015
So I was asked to present on a topic that I think is a better topic for a full symposium, so a two day symposium, which is the approach to the very, very sick patient with inflammatory bowel disease. This is a topic that’s very close and dear to my heart, the majority of my clinical work is with patients who have really broken through. I think we can all agree at this day and time that we have better options for our patients with Crohn’s disease and ulcerative colitis than ever before, however there is a subgroup of patients who despite our best efforts struggle, and we are going to focus this next 20 minutes on this topic. I would like to comment that I don’t think these slides made it into the syllabus so you are more than welcome to me at firstname.lastname@example.org, email is fine, I’d be happy to share a copy of the slides.
As you can see here we are going to be talking about not a lot of non-FDA approved options when we think about some of our patients who don’t have adequate responses. So when we think about the patient who has severe un-refractory disease we have to define that. And one of the simplest ways to define this is to think about patients who are being hospitalized. I view hospitalization of a patient with Crohn’s or ulcerative colitis in some regards as a failure. We haven’t been able to succeed with outpatient management for some reason and that person has ended up in the hospital setting.
So Jim Lewis at the University of Pennsylvania published a very intriguing study a number of years ago, 5 years ago now, where they looked at hospital admissions using the nationwide inpatient sample, which is an administrative database of 1000 hospitals across the United States. And basically they pooled the data from the discharge summaries and they compared the years of 1990 and 2003. So they hypothesis in the study was that we have much better drug therapy available for our current – for our patients in 2003 compared to 1990, what happened to hospital admissions? So during that 13 year time period Crohn’s disease admissions essentially double, and ulcerative colitis admissions rise but not quite at the same significant rate, which really begs the question why, why are patients getting admitted to the hospital at higher rates than ever before? And what is underlying the severe and refractory IBD patient?
We attempted to address this question by using the electronic medical records at UPMC, the MARS Database which many of you may be familiar with comparing the years of 1998 and 2008 in a study that was done by one of our residents from Shadyside Hospital, Marwa El Mourabet, and we compared this 10 year time period because it really represents the pre-biologic time period in 1998, Infliximab became available at the very end of 1998, and 2008 where we had multiple agents available for care of our patients. We basically looked for all patients who carried a diagnosis of Crohn’s disease or ulcerative colitis based on ICD9 coding, we looked for a number of things, repeat admissions, we evaluated for chronic pain, anxiety, depression, we looked for infectious complications, we looked at mortality. And the data that you are going to see in the next series of slides is coded as blue or red. Blue is a primary IBD diagnosis, red is a secondary IBD diagnosis that might imply the patient was admitted for some other reason but IBD was part of their health picture.
So when we compared the years of 1998 and 2008, and this is the Presby/Montefiore hospital data, and during that time period there was no increase in bed capacity so if we actually look at the rate of IBD patients who are admitted it’s a little bit under 1% in 1998 and it jumps to over 2% in 2008 and that’s a significant rise. So 2% of the 27,000 admissions that we deal with at Montefiore and Presbyterian Hospital are IBD patients coming into the hospital.
When we look at the breakdown of the disease, back in 1998 it’s pretty much a half and half split between Crohn’s and ulcerative colitis, in 2008 that’s no longer the case. There is a significant rise in Crohn’s disease, which is now 2/3 of the IBD patient admissions. When we look at the rehospitalization rate, and this is something that CMS is paying a lot of attention to in terms of reimbursement issues nowadays, so when you haven’t done a good job and fix that person and they get readmitted for the same problem there is a threat that sometimes you are not going to be paid for that person coming back to the hospital. So rehospitalization is a huge part of what we are dealing with in our IBD patients, a third of our patients in 2008 are actually rehospitalization patients coming to the hospital.
When we look at some of the comorbidities, chronic pain, anxiety, depression, neuropsychiatric issues, essentially tripling of these comorbidities which is driving many of these hospitalizations. When we look at things like surgery, I think our drugs are having a big impact, surgical rates are significantly lower over that 10 year time period. When we look at infections, Clostridium difficile, C dif, has significantly risen in our hospital over that 10 year time period with a huge impact on our IBD patients. And then here is the last slide, regarding our data which is good news, which is over our mortality associated with IBD admissions is down over that 10 year time period.
So in a quick summary, there are more IBD hospitalizations at this time than ever before, Crohn’s disease admissions are really the majority of our admissions and rehospitalization plays a really critical role in up to a third of our patients. Chronic pain, anxiety and depression contributes to the IBD patient hospitalizations and refractory inflammation despite our best efforts with immunomodulators and anti-TNF therapy I think is still an important part of what we are dealing with.
So we are going to talk a little bit about the heterogeneity of IBD and really focus on the unmet need, the patients who are still struggling. So this is a slide from Frank Netter, it’s the 1960s image of Crohn’s disease, a horrific destruction of the small intestine, you see remodeling, the scarring which is irreversible leads to intestinal blockages. The blockages create pressure, ulcers will then lead to a penetrating fistula into an adjacent loop of intestine, colon or bladder in these slides. And back in the 1960s there was really not a lot we could offer our patients on the medical side, we had Prednisone, we have Sulfasalazine, so there was really no effective maintenance therapy, so the majority of our patients, particularly the small bowel Crohn’s disease were severe and refractory because of a lack of treatment options. So the treatment was not enough, the goals of surgery back at that time period really to relieve the blockages but we knew the disease would come right back so we tried to forestall surgery as long as we could. And the results of this type of an approach don’t treat with medical therapy, and only rely on surgery for the worst of the worst complications is bad. The majority of our patients would go on to have resections if they had small bowel disease and work disability was by an NIH study in 1978 was in over a quarter of our patients.
Here is data from Copenhagen County in Denmark which really is some of the best data regarding the natural history of Crohn’s over time. What we are going to focus on here is the impact, the surgical impact on the natural history of Crohn’s over a 15 year time period. So we’re looking at all patients with Crohn’s from Copenhagen County 15 years after they are diagnosed. And what we find is that a third of the patients, 30% don’t require surgery, so there is a mild group of Crohn’s patients fortunately. After 15 years following the diagnosis a third of the patients have had one operation, and I would arguably say that’s a moderate cohort, and the last third of the patients have had multiple surgeries. Again if we look at the date of 1993, 15 years earlier is 1978 and that was back in the Sulfadine era, so when there was really no options for chronic maintenance therapy, the majority of the patients would go onto operations and if we look at the cohort here with 3 or more surgeries it’s 22%. That’s the unmet need, those are the patients we are going to be talking about, those are the people we need to identify as soon as possible, get them onto effective therapy because they are going to be doomed. Those people will be operated on again and again, those people are going to run into trouble with short gut syndrome and all of the horrific things that we can think about with that Frank Netter diagram from before.
If we think about work disability as a measuring stick to define the unmet need approximately 30% of our patients with Crohn’s disease from the same Copenhagen County, Denmark cohort ended up becoming work disabled by 10 years following their diagnosis. I can fortunately tell you that with our treatment algorithms that is down. Our work disability if we are able to get to patients quickly, early and effectively is in the 5% range, it’s not 30% anymore.
So this is a schematic of the treatment options that are available, and I want to really not focus about point in time measurements but thinking about the person’s lifetime, the long term control of inflammation and there are some people who can do relatively well with little to no therapy. I’d put that in the Budesonide, 5-ASA category, the mild cohort. The moderate patients are patients who perhaps are best served by chemotherapy based immunosuppression for the long haul, and my definition of severe disease is the person who has failed chemotherapy based immunosuppression and that person has more or less declared themselves to be a biologic therapy candidate for the long term. And surgery is really only relevant for the moderate to severe patient, so I try to give a little bit of structure to the approach to Crohn’s disease and this sort of helps to put things into, into context.
If we think about the drugs that are currently available the purine analogs, Azathioprine, 6 per capita Purine, they are pretty good drugs, they are not perfect. There is a clear separation in the Candy Wright study that we are looking at here between maintenance therapy with Azathioprine compared to placebo so about 40% of Azathioprine treated Crohn’s patients are going to do okay, that’s my expectation is a little bit under half will do well. But unfortunately that tells us that over half are going to fail to achieve remission for a variety of reasons with a purine analog.
When we think about Methotrexate there’s really seminal work that was done by Brian Fagan and the Canadian Multicenter Cooperative Trial Network back in 1995 and then maintenance data in 2000 that showed that Methotrexate is a drug we are borrowing from our colleagues in rheumatology can be effective in about 40% of our patients to induce remission, and if we think about maintenance over time there is a clear separation here between treatment and placebo. But if you actually do the math and think about the patients who are going to go on to succeed with Methotrexate it’s about 30% of those who are initially treated, there’s intolerance issues, there’s issues with Methotrexate. It’s a great drug for the person who responds but it’s not a perfect therapy and the majority of the patients will fail to achieve success with a mono therapy with Methotrexate.
Anti-TNF drugs have been available for over 12 years now, Anti-TNFs, these are the three agents, Infliximab, Adalimumab, and Certolizumab that are available for first line treatment of Crohn’s. These drugs were a huge improvement when they became available and they helped many of our patients with severe and refractory disease, and if we think about some of the evidence based medicine studies we can clearly see that the combination of Anti-TNF and immunomodulator gives us our best chances to achieve remission.
This is data published in the New England Journal from the SONIC study where just over half of the patients achieved remission with a combination Azathioprine/Infliximab approach, but again 40% are still failing. So if we use evidence based medicine we’re going to expect a cohort of our patients to not succeed. If we think about goals with healing, which is perhaps the gold standard for how we should be caring for our patients, again over half of our patients treated with combination Anti-TNF and immunomodulator are failing to achieve mucosal healing, so again a huge unmet need.
There is another issue when it comes to the Anti-TNFs which is the issue that I’m most concerned about which is durability. This is a study that we published a few years ago looking at the ability of Infliximab to be available to help our patients over time and this is a Kaplan-Meier curve, this actually shows the attrition, the loss of drug over time. So in a cohort of 153 Crohn’s patients who were on long term treatment with Infliximab as the years went by approximately half of them lost the drug by 6 years, and 80% of these patients were actually on a combination approach. So when a patient asks me do I have to be on this drug forever, that’s not the right question; the right question is how long will this drug be available to help you. And that’s need to be reframed in all of our patients. Most of the patients that we deal with are concerned about long term drug therapy for understandable reasons, but when we are thinking about that cohort of severely ill Crohn’s patients who are going to be operated on many times in their lifetime the focus needs to be on keeping drugs available, that’s the key focus we need to remember.
So when we think about the heterogeneity of IBD there is definitely mild, moderate and severe patients when it comes to Crohn’s and you see we have to think about the impact of disease over the patient’s lifetime, not a point in time measurement. That’s not the best way to think about this. The long term control of inflammation is going to require immunomodulators and biologics for the majority of Crohn’s patients, two-thirds, so you should not feel guilty about treating your patients. Monotherapy with standard immunomodulators, the purine analogs, Methotrexate or biologics as a monotherapy will fail to achieve remission in the majority of patients, and combination is going to be mandatory for long term success in part because the biologics have immunogenicity issues that impact their durability. So there is an unmet need, it’s about a quarter of our patients at least.
So if there – we need to remember that there is a differential diagnosis with IBD patients who are admitted to the hospital and this actually highlights, it’s a quick overview of all the things I have to think about. I spend approximately a week a month taking care of the IBD inpatient service at Presby/Montefiore and these are all the issues that we have to think about. Is it a true treatment failure? Is there an infection superimposed? Is there a vascular problem with ischemia, postradiation changes, NSAIDs? And we’ll go through some of these quickly.
So when it comes to drug intolerances we have to remember that many of the drugs that we use in inflammatory bowel disease maintenance are problematic. My expectation is that at least a quarter of our patients where we start Azathioprine are going to have a bad reaction. That could be something like an upset stomach, abdominal pain or something like full blown pancreatitis, fevers, horrific Lupus like drug hypersensitivity can occur in about 10% of patients. Identifying that is really important. Steroids will sometimes mask some of these reactions, so as Prednisone is lowered in these patients these adverse reactions are essentially uncovered. When the IBD patients were asked why they stopped their drug therapy 7% of them told the author of the study here that they felt worse on their drugs. So we need to listen to our patients when they tell us that the drugs are making them feel poorly, 5-ASA agents it’s a 4% adverse reaction rate, purine analogs approximately 25%, and Methotrexate maybe 20%.
When we think about the comorbidities, infections play a major role in why our patients are getting admitted to the hospital. You saw the Presby/Montefiore data a little bit earlier. So C-difficile has been the big, big problem that’s emerged over the past decade. There are over 500,000 cases, it’s probably closer to 700,000 cases of C-diff annually in the U.S. That corresponds to 15,000 deaths in the United States, it’s actually killing more patients than HIV disease is currently in the United States at this time. There’s been a change in treatment response, Metronidazole is about a 50% success in initial therapy with compared to where we’ve been in the past. And there is a huge impact on the IBD patient cohort. We’ve published a number of studies in this regard, and basically we showed that when IBD patients are admitted to the hospital with C-diff there is a mortality of 4%. So you have to make the diagnosis. Diagnostic approaches a few years ago with ELISA testing were not good, PCR is a much, much more robust test for making the diagnosis. You have about a 90% accuracy with a single PCR analysis, so think about C-diff as a contributing factor in all IBD patients who are flaring, particularly those who are getting admitted to the hospital. Vancomycin is the appropriate drug therapy to treat C-difficile in the IBD patient who is hospitalized and we really have to identify the infection quickly so that we are not using steroids in the setting of a true infection which is perhaps the major mechanism leading to death.
So when we think about this algorithm I’m going to remind everyone that surgery is an important part of taking care of our patients. And sometimes when we’ll see CT enterography like this we see these problems here, these inflammatory potentially strictured lesions in the small bowel, and we are always asking ourselves should this be a person we operate on, should this be a person where we ramp up to maximum medical therapy? There was a beautiful study that was actually done by Bo Shen’s group at the Cleveland Clinic and it was presented at San Diego this past May at the DDW where they looked at essentially 220 Crohn’s patients who had imaging studies. About half of them went on to biologic therapy, the other half did not and they created something called a Simplified Stricture Severity Score. So basically they looked for complications, was their dilation of the intestine, were there fistulas, were there abscesses, was there severe mesenteric stranding identified on those x-rays? And it turns out if they didn’t – if the patients did not have any of those complications on the x-ray findings, biologic therapy is the right answer, a clear separation here between those who went on to surgery without biologic and those who had biologic and prevented an operation. When any one of these complications was present there was no separation. So once you start to have a complicated small bowel stricture it’s probably going to be a surgery no matter what. It doesn’t mean that drug therapy is a failure, it just means that you are going to be fixing the anatomic blockage. It’s a little bit too late for intervention to really alter the natural history.
So when we think about strictures, the strictures are sometimes easy to see, sometimes they are subtle. This is a web stricture. Here is a nice small bowel x-ray study from a patient I took care of over a number of years ago. There is a clear stricture between the neoterminal ileum and the colon, but when we dredge the small bowel intraoperatively there are four more strictures, and we did Heineke-Mikulics strictureplasty and this person did much, much better. Previous operations that really just focused on that long neoterminal ileum stricture left her still obstructed.
The differential diagnosis of refractory IBD includes other illnesses and there is something called CVID, it’s the combined variable immunodeficiency, which includes hypogammaglobulinemia. These patients actually develop an IBD-like disease, it looks just like Crohn’s disease, typically a Crohn’s colitis. It’s pretty easily identified on history. Just ask your patients are you taking antibiotics a few times every year? If they say yes you need to check a quantitative immunoglobulin because IBD patients who have this mechanism leading to their disease oftentimes don’t do well with some of the more powerful immunosuppressants, so we want to identify these folks. They can be sent to immunology or allergy for guidance, they can be treated with intravenous immunoglobulin replacement. When you look at the CVID cohorts, about 7% will develop a Crohn’s like illness, and what’s also intriguing is that there is a marked, marked risk of lymphoma in these patients. So about 7% of hypogammaglobulinemia CVID patients will develop lymphoma in their lifetime, so you really don’t want to go with dual immunosuppression in a person who doesn’t really have Crohn’s but they have this other process.
There is a poor correlation between IBD symptoms and inflammation so always ask yourself could my patient be suffering from bio-acid diarrhea, are there other reasons that they are going to be causing pain? It’s not just inflammation, so always think about getting objective data, that’s really an important message.
So the checklist of issues to watch out for drug hypersensitivity, don’t miss it and remember that steroids will mask many of these problems. Always look for infections when your patients are sick, particularly C-diff. Noncompliance is an issue. One of our most severely ill patients over the past few years, we actually talked to the insurance company and found out when he had last received a prescription for his drugs, it was a year and a half ago. So he’s telling us that he’s taking his medicines but he had actually not received drugs in 18 months. Congenital immunodeficiency we’ve touched on already. Occult stricture disease is an important consideration. Dropping a patency capsule will help to identify that if you are concerned. Pain secondary to bio-acids, postsurgical diarrhea.
So if we treat our patients with severe and refractory disease there are drugs that we can turn to, none of this is FDA approved. I would suggest that you feel free to contact me, refer your patients to our center if you are concerned about moving on to these agents that are not part of the standard algorithm. Actually there is an FDA approved approach which is Natalizumab, this is a very effective strategy for long term control, the only problem is JC virus reactivation has been identified as a major contributing factor to progressive multifocal leukoencephalopathy. So we can screen for that at the present time period, which makes it actually a much, much more user friendly drug. So our Crohn’s patients who are JC virus negative can do quite well with Natalizumab and it’s a fairly safe drug to use in that setting.
There are other immunomodulators that we can use that are used more routinely in rheumatoid arthritis, in rheumatology, Leflunomide is something we’ve published on in the past. It’s a pyrimidine analog. It’s a pretty good drug for about half the patients, it’s not appropriate for pregnancy and again referral is probably the best thing when we think about using some of these agents. CellCept, used by our transplant colleagues, again it’s a modified second generation Azathioprine compound, not appropriate for pregnancy. Thioguanine is an agent that’s very effective but there is a potential for hepatotoxicity, so this is something that has to have a very careful discussion between hepatologists, the IBD docs and the patients that we are going to embark on this type of a strategy.
Pediatric colleagues have actually done something quite interesting, a polymeric diet, if your patient stops eating regular food and moves onto a liquid diet there can actually be pretty impressive results and there is some data from pediatric induction trials that’s compelling. It takes a motivated patient to embark on a strategy by giving up food, but it’s something that can be thought of in a last ditch rescue type of an approach.
When we think about our patients who are in deep trouble there are some things that we can do at the present time that are available but again this is the very sick, sick patient who is in dire straits. Stem cell transplantation has been a protocol at Northwestern, it’s been done by our colleagues here at Children’s Hospital for refractory patients. TPN is something we are very well acquainted with, we have a very active TPN service at Presby/Montefiore and we have approximately 34 outpatient TPN patients, approximately 20% of whom have Crohn’s disease. Small bowel transplantation I think we are still the biggest center in the United States when it comes to this. I see patients with Crohn’s who come from all over the country for small bowel transplant. Again it’s a last ditch effort to keep them alive.
But I want to finish up by just touching on a couple of quick concepts with personalized medicine where we are headed. So inflammatory bowel disease is perhaps the best example of gene discovery. So the GWAS studies that have been done by Rick Duerr and the colleagues throughout the world on the Genetics, IBD Genetics Consortium, have identified over 170 genes that are linked to inflammatory bowel disease. There has been some data suggesting that the genetic profile of your patient can predict the future. My former colleague and close friend Subra Kugathasan showed that a NOD2/CARD15 mutation in a child characterized at the time of diagnosis actually predicted who went on to rapid surgery. So this is a C insertion mutation. So there actually may be a crystal ball on the molecular side to help us guide our therapy in our patients. We know from basic science that Interleukin 10 is a very powerful molecule to turn off inflammation but huge studies done on IL10 in Crohn’s disease failed but the reason I’m telling you about this is this publication that was in the New England Journal back in 2009 there was a severely ill child with Crohn’s disease in Germany who had a unique mutation in the IL10 receptor, so this was a child who had a personal version of Crohn’s disease that they could characterize. And this person, this young child was treated with a bone marrow transplant which eradicated the disease.
And I’m going to end with this slide, which is a Pulitzer Prize Winning story that was published in the Milwaukee Journal Sentinel. The little child that you are looking at over there on the right is Nicholas Volker, he’s 6 years old in this picture. His mom is over on the right and he’s doing a high 5 with Dave Margolis who is a pediatric bone marrow transplanter at the Children’s Hospital of Wisconsin. Nicholas Volker was hospitalized over 100 times, he spent most of his life up to age 6 in the hospital, Children’s Hospital. He was found to have a unique mutation in a gene called the Inhibitor of Apoptosis Protein which is on the X chromosome. Because he’s an XY male the mutated gene had no help, there was no second X copy to keep him functioning and he had horrific, horrific Crohn’s disease, failed all forms of therapy. My former colleagues in Wisconsin went on to do whole exome sequencing, they characterized the gene mutation. They realized he had a personal version of Crohn’s disease that would never get better with any of the standard drugs. He received an autologous stem cell transplant and was cured.
So that’s the future of inflammatory bowel disease. Every patient is going to have their own version of the disease, we have to accept that. When we look at things as big lumps based on ICD9 coding we are going to fail for our patients who have severe and refractory disease. We’ve done whole exome sequencing on 10 of our patients, everyone has 1000 unique mutations. That’s the reality of personalized medicine. It’s going to be a challenge to actually figure this out. Dave Whitcomb is perhaps one of the top people in the world in terms of thinking about genetics and phenotype, but that’s where we are going to be headed.
So I’m going to wrap things up. Severe and refractory IBD is common, between 20 to 30% of our patients will fail to respond to standard agents, hospitalizations for Crohn’s have risen in recent years despite our drugs, and multiple contributing factors can include pan anxiety and depression. Over half of Crohn’s patients will fail to maintain remission with immunomodulator monotherapy, Crohn’s patients who are intolerant or fail standard immunomodulators are candidates for long term biologic treatment. Durability of biologic therapy is limited, and that’s an important part of our discussions with patients. The differential diagnosis of severe and refractory IBD includes infections, congenital immunodeficiency, adverse drug reactions, ischemia and refractory inflammation. Available immunosuppressants can be considered, these are agents that are prescribable now but I feel comfortable doing this after a nice discussion with our patients but it’s something we can offer at the present day and age. Natalizumab is an FDA approved agent that we can screen for complications with the JC virus serology that’s become available and that’s an option for our patients. When things are bad TPN and small bowel transplant is still available and improved care and cost effective care will lead to development of a personalized approach which addresses the unique inflammatory mechanisms and the identification of fetal care so we can do things like bone marrow transplants, and then considering referral to an academic center when you are dealing with these types of tough patients. Thank you for your attention.