During this 20-25 minute pre-recorded lecture, Dr. Robert Hirten discusses the topic of IBD mimickers. This in-depth review will provide an update on this topic for your clinical practice as well as supplement your learning for the ABIM Gastroenterology and Hepatology boards.
blue. My name is robert hurt and I'm one of the gastroenterologists at Mount Sinai Hospital with a focus and inflammatory bowel disease. And over the next 20 minutes or so. I'm going to be speaking to you about IBD mimic er for my conflicts of interest. So the brief overview, we're going to be speaking about conditions that can mimic inflammatory bowel disease. Now this is a very diverse, large group of conditions we're going to focus really on three primary ones to emphasis, particularly as it relates to the board. These are microscopic colitis, segmental colitis associated with that particular Asus and medical medications which can result in balance injury which can can frequently mimic and flat balance seeds. Now we're thinking about inflammatory bowel disease and we're seeing patients who we might be thinking that this could be the underlying cause of their symptoms or the endoscopic findings. It's very important that we maintain a very broad differential diagnosis and I've included in this slide a number of the different conditions that could mimic inflammatory bowel disease, both in symptom ideology or an endoscopic appearance. And whenever we're seeing these people, we want to think of course about infections as a predominant cause of the symptoms that people are experiencing. We want to think outside the Gi tract. So as gastroenterologists are very focused on the Gi tract but we always want to be thinking about adjacent organs in the abdominal cavity that could be resulting in symptoms or appearances that look like IBD such as tubo ovarian disease for example, we wanna think about vascular ideologies um for symptoms or endoscopic findings or imaging findings, particularly in the right population. So older older population where those with underlying vascular disease. Think about small Dalmiya plasm metastatic disease. Um that involves the GI track infiltrated conditions, drug induced conditions or viewing the drug lists of the patients that we're seeing, seeing what might might be resulting in a particular finding we're seeing in that patient radiation injury, immune mediated conditions, uh inflammatory conditions like segmental colitis or microscopic colitis, graft versus host disease and solitary rector collectibles. We're going to first focus on microscopic collects. So microscopic colitis is a group of idiopathic disorders mainly affecting the colon and it's characterized by chronic watery diarrhea, grossly normal kaleidoscopic findings and a very characteristic history pathology. So in lymphocytic colitis, what we end up seeing is sub epithelial lymphocytic infiltrate without excess collagen. In colossians clients, we see a thickened sub epithelial collage, this band with an associated mono nuclear cell infiltrate. As for the epidemiology of microscopic colitis colitis colitis is president of the 10.8 people per 100,000 Olympus. It'd colitis is a little bit more prevalent. Up to 14 people per 100,000, the incident appears to be rising as well in the general population based on large population studies. When we look at the prevalence of these conditions, it's as high as 219 per 100,000. When you look at large international population based studies, it's important to remember that there is a female predominance with microscopic flights. And this is particularly most pronounced in collage this colitis Where the female to male ratio, that we could see it as high as 7-1. The incident also is increasing increases with age. So the average age we're going to diagnose someone with microscopic colitis is approximately 65 years of age. The most common ages of onset are 50-70. But it's very important to remember that. Up to 25% of people with microscopic colitis can be under the age of 45. This is particularly important when we're thinking about, uh we're seeing patients in the office who were thinking could have perhaps irritable bowel syndrome even. And we always keep this differential in the back of our minds. Usually it presents with chronic non bloody watery diarrhea could be up to two L per day. Most patients will have between 49 bowel movements per day, but in severe cases it can be in excess of 15 bowel movements per day. Typically the diarrhea is intermittent though it can be continuous and about 40% of patients will actually have a sudden nonsense of these symptoms as opposed to a more insidious kind of gradual presentation. Common, commonly urgency, fecal urgency will be reported abdominal pain, weight loss, nocturnal diarrhea, all in over half of patients incontinence can be prevalent. President up to 40% of patients. Um and while these are based on an older study where they were using Rome two criteria, 43% of patients with microscopic colitis will fulfill Rome two criteria. Again, to my earlier point where we're thinking about irritable bowel syndrome and someone it's important to consider microscopic colitis in that differential. And we can also see weight loss with this, but in that case it should sort of trigger in our minds perhaps because they have concomitant celiac disease, which should be ruled out as these two can often go together specifically when when we're seeing weight loss, there are a number of important associations that are related to microscopic colitis that are that are not only important for our clinical practice, but also for for boards, these are kind of favorite topics. Um There can be a number of associated autoimmune diseases with microscopic colitis. It's important to note that these will often precede the diagnosis of microscopic colitis. Um but but nonetheless can be present. Um the conditions that we we see are that are frequently present includes celiac disease, autoimmune, thyroid disease, show grins diabetes, probably my al jerome attica psoriasis and of course, irritable bowel syndrome, which can overlap medications are important to keep in mind as well. Drugs act as an environmental risk factor and in fact this is most prevalent with PPS and incense. But here I've included a list of other medications that are very commonly associated with it. Now, the associations are one thing and it's important to remember that a lot of these medications can result in diarrhea themselves, which could prompt evaluation of patients with colonoscopy leading to the histological diagnosis of microscopic colitis. But nonetheless, there is an association here between these medications and it's developed. So how do we make a diagnosis of microscopic plays? Well. First patients would have chronic diarrhea, which will be key and then we perform a colonoscopy as part of the evaluation of this diarrhea. What's usually found is a grossly normal mucosa. Their can be non specific findings such as redness, edema or even some try ability. But usually it's going to look normal. This disease is patching nature. So it's very important to take biopsies throughout the cold, throughout the colon. Now, the ideal location for these biopsies, it wasn't 100% clear. And there was a recent study that came out this past year. Further looking at which portions of the colon we should be biopsy for the highest yield. There's an older studying cloudiness colitis where the highest steel was found in the transverse colon and the right colon. You know. But I think the take home point from this is that since it is Apache disease, we just need to be sure that we're taking multiple biopsies throughout the colon and being sure to take biopsies from the right colon where the yield seems to be higher compared to the left colon based on some expert opinion opinions. It's recommended to take at least eight biopsies from throughout the colon. But again, as as I was mentioning, I think we need to just make sure we're doing a colonoscopy as opposed to a flexible sigmoidoscopy. To be sure we're evaluating the whole colon and the ilium. Since I. B. D. Might be in our differential which can can preferentially favor the terminal ilium and taking biopsies throughout this is a history pathologic diagnosis. So the important thing is that we get the biopsies for the pathologists to review and that they can tell us. Do we see the characteristic features of microscopic colitis for collagen is politis What will be seen as a thickened sub epithelial collagen is banned is usually greater than 10 micrometers and has a slight increase in intra epithelial lymphocytes which could be present. Also histological e Lymphocytic colitis. On the other hand, we also see a more pronounced increase in intra epithelial emphasize at least greater than 20 for 100 surface epithelial cells. And in this case we don't see any collective band that's present. The treatments are predominantly aimed at improving simple achieving clinical remission and improving quality of life. Clinical remission is defined as having on average less than three stools per day and an average of less than one watery stool per day. There is no current evidence that we need to be aiming for histological remission. So improving actually the biopsies such that if we if we go in after treatment we're not seeing any of the histological features. Microscopic plight is present. Present President any longer. Our initial steps involved discontinuing any medications that could be associated with microscopic colitis. As we as we discussed a little earlier smoking cessation is very important as is associated not only with an increased risk of developing microscopic colitis um and also an earlier presentation of it. Um So it's it's quite important that we encourage people who are smoking will have to stop smoking. We also want to rule out internal alternative diagnoses. So we want to look at our think about our differential of conditions and make sure not missing anything else. And then start symptomatic treatment um with anti diarrheal. Now this could be sufficient for mild disease. This might be enough enough by itself to give for example a modem to help with it. But in those that it's not we'll have more significant symptoms. We want to think about which agents we could be starting to help improve improve their symptoms and quality of life. The A. G. A. Came out with a set of recommendations based upon this in their most recent set of guidelines. Um The first line therapy should be be Destiny side and this is because we have the highest quality of evidence for this agent. Mostly because we have multiple randomized controlled trials which show a benefit of using the Destiny to treat microscopic lights. I've listed some of the key ones here. We can see particularly for induction of remission. There was a large multi center double blind randomized control study that compared to Destiny masala meaning placebo. And when you look at eight weeks clinical remission rates, you see significantly higher rates in the Destiny group as high as 80% compared to only 32% and 38% in the Miss salome and placebo groups, respectively. When you look at long term maintenance of our mission, Similarly, in randomized control studies, you see similarly high rates of efficacy And after after eight weeks of induction um subjects were randomized to get either predestination or placebo for 12 months. And what we end up seeing is clinical remission rates at one year over 60% of the destiny group compared to just under 17% in the placebo group. Um and similarly meta analyses that have looked at multiple randomized control studies um for microscopic colitis found with the destiny you have an over 80% response rate for induction, a number needed to treat to um and a threefold increase in patients who are able to maintain clinical response. So really quite strong evidence for its use. Now, whenever we're considering using a steroid long term like your Destiny, we do need to weigh the risks and benefits of long term steroid use. So this is important to consider your patient population. I wanted to touch briefly on bismuth. Um This is by the A. G. A. Is recommended potentially as a second line treatment in patients who maybe can't use buddhist Sinead. There isn't as robust of evidence for the use of of this myth. There's one randomized controlled trial of only 14 patients. We were given 8 262 mg tablets per day. In three divided doses for eight weeks compared to placebo. Seven of the patients in the intervention arm compared to none. Zero in the placebo arm showed clinical response. This is a good result. But again, this is only in 14 people there for the AJ recommends that due to precision large Hilbert an impossible toxicity that we can see with long term bismuth use. Um It's recommended as a second line alternative agents. I want to briefly touch on the sala means while some of the retrospective evidence hinted at possible efficacy of this agent, there was one randomized control study that was done in 62 subjects which showed no difference in clinical remission or histological response rates with this medication. And really um there's not really enough evidence to support its use regularly in the treatment of microscopic colitis. Um And similarly, I didn't mention the slide here cola star. I mean as well, no difference in the effects were seen with the juice um as well. So it's not recommended according to the A. G. A. And in current guidelines as a primary treatment for this condition. This algorithm nicely summarizes microscopic colitis treatment. Um When you can see here is someone at the top of the slide with active microscopic colitis. As we talked about. We want to consider drug induced microscopic colitis alternative diagnoses smoking cessation which we have mentioned. And then you're going to want to start a medicine. I need nine mg per day For a few months 6-8 weeks frequently after this you could stop it and see the effect the long term effectiveness. It was brief course of steroid treatment for those that relapse. You can restart the bds 99 mg per day and then just slowly try to taper this to the lowest effective dose to minimize the amount of steroid that someone is um is being exposed to and for those that have no response to to be denied. There there is some smaller evidence to support the use of anti TNF immune modulators and other medications to treat microscopic colitis. For example last year in J. C. C. Um there was a series of 11 patients who were treated with anti vo to treat microscopic colitis of whom Five of them five of the 11 demonstrated clinical remission after three infusions. So this should be considered for people that really are not be destiny responsive, doing poor poorly and that can be managed perhaps with some of these other as given treatment such as the addition of paramount to even do destiny treat. I just wanted to go over a quick question. So uh to kind of um review what we just discussed regarding microscopic colitis. So, a 30 year old woman with a history of reflux presents for evaluation of her diarrhea. She describes what the six water abdel movements per day over the past six months, denies bleeding, weight loss, abdominal plane travel or medications include land. So brazil, laboratory infectious work up around revealing colonoscopy is performed and is grossly normal. Random biopsies revealed the following findings in the transverse colon. You have her discontinue Harlan soap operas all eight weeks later, she reports resolution ever since. What is the best next step in her management? A starting salary in 4.8 g daily for eight weeks and decrease this Destiny nine mg daily three weeks. This myth eight tabs daily for eight weeks than stopping therapy and monitoring for recurrence. Where no treatment is required to consider repeating her colonoscopy to document histological normalization. So in this case, the correct answer will be deep. And this here we're getting at the idea that she has a medication induced microscopic colitis in this case induced by land soap is all very common culprit. And the fact that stopping this medication resulted in improvement of her symptoms lends credence. This idea that this could be medication induced, No treatment would be required and she's symptomatically improved. But consideration for repeat colonoscopy, who would not be a bad idea to document histological normalization and confirming that link between the medication, Land soap operas, all the development of this microscopic colitis and then a subsequent resolution. Now we're going to shift gears a little bit and start talking about segmental colitis associated with diverticular Asus. So santa clara associate with diverticular Asus is characterized by inflammation and the inter diverticular mucosa without involvement of the diverticular orifice. Its epidemiology. Uh it's present in subjects with diverticular aosis in about .26-1.5% of the time, the mean age of presentation in 64 years and it's slightly more prevalent and then compared to women. Now, the pathogenesis of this is not clear. There have been a number of different proposed mechanisms from which it could develop, including new cultural prolapse around the diverticular, resulting in shear stresses and inflammation fecal stasis around diverticular, causing changes in bacterial flora, inflammation, permeability to intra Luminal antigens and inflammation, altered mic micro vascular circulation around diverticular, causing focal mucosal ischemia and subsequent inflammation. But really, the bottom line is that while he's been proposed, we don't really have a great idea of what the cause because of this adds the symptoms can range from being asymptomatic, where this is just incidentally found on a colonoscopy to having chronic diarrhea abdominal pain and Hamasaki asia, which are the three most common symptom and when patients report abdominal pain, they'll usually described as cramping and in the left lower quadrant and up to one third of patients will actually report having two of these three symptoms, Either chronic diarrhea, abdominal pain or from anesthesia being present At the time of diagnosis, there have been various attempts to try to take what is a fairly heterogeneous condition and try to put it into some kind of grading scheme from which we could we could evaluate um segmental colitis um in a more meaningful way. And here this is the most commonly presented way to group different findings of of segmental colitis um into into a grading pattern. And with Type A disease, we see chris centric fold pattern and this is where we see these reddish round lesions that could be up to 1.5 centimeters in size seen at the top of the colon folds. Um it's present in about 52% of patients and this is one of the most common finding. Um Type B, which looks very much like all sort of colitis. You see a loss of sub mucosal vascular pattern, oedema of the mucosa Hibri me A diffuse erosions. President, about a third of patients, Type C looks a bit more questions like where you have isolated at this ulcers and type used to see severe also collide. It's like pattern where you have some coastal vascular pattern that's completely lost of hyper Rania. Diffuse authorization ulcers and reduce colon aluminum. This is probably the rarest at 6.5%. Now, more than 80% of all these lesions will be found usually in the sigmoid colon where we tend to find um tend to find a ridiculous is very treatments are not well defined. The majority of patients have been reported to respond well to medical therapy, though a third can relapse in three years and some can develop even chronic symptoms. Now this is really based these treatments on expert opinions, but a lot of these uh these um these recommendations can be even even presented to the board exams of how to approach it. But but I would like to stress that there isn't a lot of evidence to support this treatment modality. Initial treatments generally are recommended to include a brief course of antibiotics, usually for 10- 14 days. Cipro and fragile being the most common. Relapses can occur and if there's inadequate response or the patient relapse is a treatment of Miss salome 2.4 g for 7 to 10 days, increasing to 4.8 g can be used. Uh And and one small study, 80% of patients who were treated with the fax. A minimum salary for 10 days at the missile Amigos being 2.4 g per days and then transitioned to eight weeks of salami, 1.6 g per day. Had complete resolution of symptom. Yeah, there's no response to this therapy. A brief course of steroids can be considered predniSONE for six weeks and there is limited data for other immunosuppressive agents. Now, what I say is on the previous slide I showed you a very diverse form of presentation with which with which scad and signature clays can manifest. So I would really tailor in clinical practice my treatment based upon these endoscopic findings. It's one thing to have a patient who has just small areas of patchy erythema in this, in the sigmoid colon, say around in particular, which is resulting in symptoms and another one to have significant dip alterations in this area. And I certainly would modify my treatment regiment based on that and perhaps with the more severe disease of the colon and the intestine these areas. I my favorite treating even even more upfront aggressively as we would in inflammatory bowel disease. Even with biologic agents and other other immuno suppressive agents. A question now to kind of go over what we briefly talked about with scan a 50 year old woman with four months of left lower abdominal pain and diarrhea presents to the office. Her cT scan demonstrates no abnormalities. Colonoscopy is performed really revealing the below findings. But you can see picture here you're seeing some patchy era fema in the colon biopsies reveal chronic inflammatory changes. The patient has no other medical history denies maddock asia weight loss or fevers. What is the most appropriate treatment for this patient? A start your destiny nine mg daily for eight weeks and then slowly taper therapy start is a diaphragm, two mg per kilogram of body weight Start Cipro 500 mg twice daily and fragile 10 mg per kilogram per day for 10 to 14 days. Or recommend a high fiber diet and avoid seeds and nuts. And the answer is we discussed with these initial treatments. A brief course of antibiotics would be the best first treatment with Cipro combined with fragile for 10 to 14 days to judge effect. And in someone in this case was much more mild endoscopic findings. This would be a much more prudent for a step in starting say long term immuno suppressive therapy such as a as a fire. Now we're going to be speaking briefly about drug use, val injury. So first we want to talk about immune checkpoint inhibitors. So these are medications that target set a toxic T lymphocyte associated protein four and also PD one PD L. One. They enhance anti tumor T. Cell activity. Evelyn A mob is one of the more common agents that's used for melanoma. It's an anti C. T. L. A. For antibody. No Villa mob and temporal is a mob or anti pD one. Um While at the cell is a mob of aluminum mob and Derval A mob are anti PD L. Ones. These can be treated used to treat a variety of other cancers including melanoma, gastric cancer, Hodgkin's disease. I'm as well. Um There's a number of gi side effects that are very commonly associated with these medications with anti pD one agents. We see diarrhea present in almost 14% of patients Colliders can develop in just under 2% of patients. We see this more likely in subjects with melanoma. The anti C. T. L. A. Four agents we see diarrhea and up to 35% of patients. and colliders can develop in up to 9% of patients. And we see a number of different features that are associated with an increased likelihood of developing colitis with this agent such as higher doses of the medication certain microbiome features. I'll um 17 levels increase the cynical accounts and pre existing I. V. D. The timing of symptoms can be a bit varied with the anti CTL A agents. We can see the development enter colitis on a median time of onset being one month from medication initiation but a maximum up to two months after the last infusion. So for quite a long period of time with anti PD one agents it's it's we see it usually 2 to 4 months after the first infusion. With a maximum being up to one year after medication in education. The presentation of this condition um includes abdominal pain, knowledge of vomiting, diarrhea, maddock asia. You can have also mouth lesions and anti PD one agents and disc optically. You can see here with the anti C. T. L. A. Four agents up to 79% will have alterations. Two thirds will have extensive colitis. Um Up to 79%. Um We'll have continuous inflammation present. Don't colonoscopy in 12% will have really itis with anti PD one agents we see Apache distribution and up to 75% of patients. Two thirds will actually have abnormal upper gi endoscopy as well. With the 10.5% developing necrotizing gastritis. So when we're thinking about these adverse events that are happening in these symptoms that are happening with these agents um Most of the recommendations recommend grading these events based on the national common terminology criteria for adverse events which grades grades both the diarrhea and the colitis. On a scale of 1 to 41 being the most mild for being a really life threatening. Very severe. This is from a nice review article from got from a few years ago they tried to put the available evidence together um to give some treatment recommendations on how we should approach this. So first anyone that's presenting who's on these agents with diarrhea or science politis we want to do the usual blood work. Crp check thyroid function. C. M. V. P. C. Are just nation that this isn't a co infection and then still tests um to make sure they're not having c diff or another enter a pathogen complicating the picture if there are symptoms are generally miles a grade one or two. You could rely on symptomatic treatment like a low fiber diet oral fluids and paramount. If they don't improve or if they have grade three or four diarrhea or colitis it would be prudent to consider doing potentially a colonoscopy with biopsies and of course if they're very sick getting abdominal imaging or considering a surgical consultation for the treatment of grade one or two lesions. Oral predniSONE at 20.5 to 1 mg per kilogram per day or just 99 mg per day. Could be considered for persistent grade one or two symptoms. Despite this or a grade three or four symptoms. We would recommend starting oral predniSONE and if there continues to be persistent the symptoms consider starting I. V. Metal predniSONE at one mg per kilogram per day. If there's no improvement or worsening within 3 to 5 days of this initiation of inflicts. A map would be important at this point. Um And this can be repeated two weeks later if needed. And this is something that the boards frequently. We'll talk about the music. A question that this on this topic. A 50 year old man with metastatic melanoma is started on april um Ahmad six weeks after starting therapy, he develops diarrhea. Full studies are negative for infection and he started almost paramount. He sees you in the office reporting no improvement and up to $7 movements. Daily CT Scan revealed left sided colonic thickening colonoscopy reveals extensive colitis with patchy ulceration seen throughout the rectum, sigmoid descending and transfers colon. If golimumab has stopped the patient has started an intravenous corticosteroids in his transition to predniSONE 40 mg daily after five days. You know, it's resolution of his diarrhea while I'm pregnant. What is the next best step in his management? A since the patient has responded to friend, his own initiate vandalism. Ab be slowly taper predniSONE. See initiate inflicts a map to treat people in a mob induced colitis. D. Start the Salomon 4.8 g daily and continue this for three months after completing the predniSONE. And the answer is b slowly taper the predniSONE. So in this case the patient is responding to the medication the predniSONE, the epidemic map has been stopped. So this at this point we would start decreasing the dose of predniSONE slowly and monitoring the patient for continuing improvement of their symptoms. He should last thing I wanted to just talk on briefly as well. Uh and set induced injury. This is something we very commonly see and can a very common mimic of inflammatory bowel disease. The epidemiology of this. Two thirds of patients who use N sets demonstrate intestinal inflammation on indian scans. 50% of insight users compared to 5% of controls have been found to have small mucosal breaks. For example, in studies of valuing the small mucosa, for example, of capsule undocks appease. This can present very variously from asymptomatic from being asymptomatic, having abdominal pain, diarrhea, nausea, anemia, weight loss, obstructions or hyper album anemia. Now the pathogenesis of this is it's a bit diverse. It can be related to just localized injury where the medication itself is causing a local injury verse uh its effects on the inhibition of prostaglandins which result in alternative cultural profusion and then subsequent increased permeability and damage from oxygen radicals um causing micro vascular constriction. Now the endoscopic findings can be fairly diverse as well. What is very catholic pneumonic for this though? Our diaphragm like structures which we see which is likely from a scarring reactions secondary to ulcerative injuries. These are thin concentric diaphragms that look like a septa with pinhole sized lumens. Usually they're found in multiples in the val um and they're characterized by sub mucosal fibrosis with either a normal overlying mucosa or just some alteration at the actual tip of the of the narrowing. It can be very difficult to diagnose on imaging and you can see it here because it can appear to be exaggerated plato circularity. The intestines which can make sometimes picking this up on like an entourage, graffiti a little bit more challenging. In addition to these narrowings we also can see um alterations that can happen in the colon or the small intestine or even in the in the upper gi track histology can be either non specific or it can actually have chronic changes as well which could mimic. And a pure like inflammatory yeah treatment discontinuance sets um If you have any doubt or question that could the inflammation you're seeing in the intestine be inset related as opposed to I. V. D. Related. You can stop the medications and then 6 to 8 weeks later 12 weeks later redo your endoscopic assessment to evaluate for resolution of the inflammation and the persistence of the inflammation. Then we kind of raised the suspicion disease. You have any of the narrowings that are present. Endoscopic dilation could be undertaken for these structures or if obstructions are happening from these laparotomy surgery. The last point I want to quickly touch on is michael Fennell it induced injury. Um So this this is commonly seen as well. So these agents inhibit lymphocyte proliferation. They're often used to prevent acute telegraph rejection and glucocorticoids during agents and a number of conditions including rheumatoid arthritis and lupus. There's two formulations there's a michael Fennell late formulation Cell Sap which is the pro drug with improved bio availability. Then there's the enteric coated formulation my for dick which has a delayed release to the small intestine to improve gi side effect profiles. Now the symptoms I could develop from this are very varied including Diarrhea, Nausea, vomiting and abdominal pain can occur even up to 75% of subjects who are on this and can be a very limiting factor. Um uh in the use of this medication. Endoscopic lee you can see ulcers, edema or erythema or actually even even a normal endoscopic appearance. Um But there can be very very histological findings that could be that could be there that can make this a very diagnostically challenging um conditions since it can mimic so many other conditions. And you can see histological findings that look like breakfast host disease I. B. D. Like patterns ischemic like injury or sort of these these self limited pattern that you might see with increased neutrophils, preserved architecture um that are there present as well management. Um What you can consider doing is increasing the number of daily doses that the person is on while maintaining the total number of total daily dose of the medication. If that doesn't work, you can reduce the total daily dose um to see if this can improve the side effect profile or you can switch the enteric coated formulation if they're not on this. There was one open label Multi Center study of 111 subjects who were who were switched to the enteric coated formulation and noted significant improvement in quality of life scores and gastrointestinal symptom rating scores as well. So that's also a very good good treatment option.