In this update on inflammatory bowel disease, gastroenterologist Kendall Beck, MD, notes contributing causes, explains which tests have value, gives keys to distinguishing ulcerative colitis and Crohn’s (as well as the many conditions that mimic IBD), and delineates the benefits of early detection and aggressive intervention. Included is a rundown of pharmaceutical options, including biologic agents, with important notes regarding safety, along with general screening recommendations for IBD patients, who have a higher risk of numerous other conditions – from certain cancers to cardiovascular disease to depression.
Sure. Thanks for having me. Um, so my name is Kendall Beck. I am an assistant professor at UCSF in the GI division, and I'm the ambulatory medical director there. And I also, um, see patients at, uh, at the San Mateo Clinic. And yeah, I'm happy to talk to you about kind of IBD management and primary care today. This can be a very kind of open discussion. Hopefully, hopefully folks have some questions and um I can hopefully answer them. So, let's see here. I have no financial disclosures. Um, we'll kind of give a quick overview of IBD with epidemiology, etiology, thoughts on etiology anyway, um, diagnosis, current treatments, and then we'll try to spend most of our time on general medicine, um, considerations in the IBD patient. First, I thought it would just give an overview of uh the UCSF, uh, kind of colitis and Crohn's Disease Center, um, so that you can put faces to names if you do in fact send your patients to us. There's one doctor who's not pictured because she just recently started. Her name is Rishia Chug, and so she will be seeing a lot of our IBD patients as well. Not everyone goes to the San Mateo clinic, however, um, Doctor Turdeman is our, uh, chief of our gastroenterology division. He, he is not seeing patients at the San Mateo clinics, but he is, uh, you know, sees patients from all over the Bay Area in California. Doctor Mahadevan is our, uh, director of the colitis and Crohn's Center as well. And doctors Elnachef, Doctor Lewin, and Doctor Rajapatna, they are also in our IBD group. They neither of them goes to the peninsula to see patients, but, um, they certainly also see patients from all over. Doctor Kata here, he's an MD PhD. He has an active research, uh, career but also sees, um, IBD patients and he has a clinical focus in, um, Really patients, young patients that are transitioning from the pediatric GI world to the adult GI world. So if you ever have any patients that are kind of just transitioning from pediatrics to GI and have IBD, uh, he's our go to and um, he does see patients within the San Mateo clinic. And then, uh, myself, I also, uh, see patients within our San Mateo clinic. And so our, our, our physical address, um, is, you know, 1100 Park Place. You may already know this from referring patients there before. Um, like I said, just Doctor Kata and myself see patients there. We have about between us two half days per month of IBD focused patient clinic. Um, We can see, uh, follow-up patients that are on the, you know, that live on the peninsula that don't have IBD, um, but are following up, but all the new patients should really, uh, be IBD based if they're being referred to San Mateo clinic. That all being said, right now we're actually still doing all of our uh visits as virtual visits um for the San Mateo Clinic in particular, and so, um, you know, the experience would be the same for the patients at this point. So just a kind of a quick overview of IBD itself. Um, so there are greater than 2 million people in the country living with IBD. Um, the, the, uh, two most common forms of course are ulcerative colitis on the left and Crohn's disease on the right. We do have a certain, uh, small percentage of patients that we kind of consider indeterminate colitis. They, they may have features of both. Um, but most of the time we're able to pin it down. Um, with ulcerative colitis, it's mostly distributed. Through either just rectal involvement, proctitis, uh, left-sided disease, which is about 25%, and then the majority of our patients have pancolitis, close to 50%, so involving the whole colon. With Crohn's, we also like to denote the, uh, distribution with um whether patients have just ileitis or I would actually say, you know, small bowel Crohn's disease. And then whether they have small bowel and colon involved, which is our most common 45%, and then colitis, 32%, um, those that have only colitis. Of course, with Crohn's, as you all might know already, uh, the, um, the one of the major differences besides the fact that it can involve anywhere in the, in the, uh, intestinal, gastrointestinal tract versus ulcerative colitis which only involves the colon, uh, Crohn's patients also can develop fistulas and strictures and abscesses and that's due to the transmural inflammation throughout the bowel, um, and so that is one of the other major differences between the two conditions. So we, we don't know, we still don't know exactly why patients, uh, develop IBD, but, um, the current hypothesis, you know, is of course that it's multifactorial and the, the diagnosis or, or the development of IBD exists when the right kind of genetic predisposition interacts with alterations in the immune system and environmental triggers. Um, these environmental triggers may have something to do with, uh, uh, factors with early childhood diet, early childhood infections, or antibiotic exposures, um, which may alter the microbiome, but I, but unfortunately, we don't have great causal links yet on any of these issues. We do know that, uh, smoking, uh, certainly, um, Significantly increases the risk uh of of Crohn's disease. However, um, we actually don't know for sure whether smoking, sorry, whether smoking Technically increases the risk for Crohn's or whether it's kind of a mitigating factor in, in that it actually can or sorry, excuse me, exacerbating factor and that it can exacerbate disease and that's because, um, just if smoking was a causal factor, then it would not explain why some countries in the world that have the lowest incidence of smoking also have one of the higher incidences of IBD such as Canada and Sweden. And the converse is also true that um many countries with a high rate of smoking have lowest uh rates of IBD and so it's probably more likely that smoking is maybe not a causal factor, but more a modulating factor. Um, we do know that, uh, smoking can increase the risk of kind of, um, more severe Crohn's disease at the very least, or, or developing post-operative recurrence or, uh, kind of minimizing the response to our medical therapies. There is data that shows that actually having had an appendectomy is protective for the development of ulcerative colitis, though I will say the relationship is less clear for Crohn's disease. Uh, antibiotic use, as I alluded to before, has been implicated. There were, there were some studies in the last couple of years that showed that greater than 3 dispensations of antibiotics in patients increase the risk of, uh, Crohn's and UC and of course the broad spectrum, the, the broader the spectrum of antibiotic, uh, the higher the risk of developing IBD. There was also a recent study that showed that actually statin use, so patients who are on statins had a lower risk for Crohn's disease. And then one thing just to note because this is kind of an old wives' tale of it or or a theory from many years ago is that vaccines and is retinoin are not associated with the IBD development, whereas, um, you know, many of, several of our patients have come to us asking about that. Unfortunately, these are all just causal studies and or I'm sorry, asso association studies and not causal, do not establish causal links. Um, there have been other studies looking at diet, um, particularly recently, this is becoming a hotter topic, um, at our DDW conferences and in this study basically showed that, um, Patients that had a higher consumption of sugar-sweetened beverages had a somewhat increased risk. Um, of Crohn's disease, although it was not as statistically significant. In a separate study, uh, they showed that a pro-inflammatory diet, which is kind of defined as a diet that's high in red meat, refined grains, and sugar-sweetened beverages, uh, did increase the risk of Crohn's disease by a bit with a hazardous ratio of 1.06 to 1.99, um, but did not find a difference for, uh, UC in patients that, uh, took this type of diet. Um, a separate study looked at this again and showed that artificially sweetened or natural juices, um, in, uh, sorry, uh, did not increase the risk for Crohn's or ulcerative colitis. However, um, they did show that sugar-sweetened beverages, uh, greater than one unit per day did increase the hazards ratio. Um, Of developing Crohn's or I, I guess developing IBD in general. However, this P value is not statistically significant, but when you broke it down into Crohn's and UC, they again saw this relationship of Crohn's. So patients, uh, drinking beverages that are high, that are highly sugar sweetened, um, were more likely to develop Crohn's along the way, and that's shown here. This is patients who drink more than one drink, uh, sorry, one drink a day. Um, did increase the IBD risk. Move on to talking about uh the diagnosis of IBD. Signs and symptoms are very similar between the two. Either can present with bloody diarrhea, tenesmus, abdominal cramping, and weight loss. Um, In addition to extraintestinal manifestations such as uveitis, joint, you know, joint pains or inflammatory arthropathies, other conditions like skin conditions, um, erythemanodosum, pyoderma gangrenosum. Crohn's disease may be more likely to have to, for patients to experience weight loss, um, along with it. Also, they, they are going to be more likely to have perianal disease, um, and in children, failure of normal growth can be the presenting sign of really either of these. It's important to always remember that there are mimickers of IBD, so that includes infections, especially fungal infections. There's a, uh, chronic variable immune deficiency can also present with, uh, small bowel inflammation that can mimic Crohn's. Um, other infections that kind of like the terminal ileum and cecum area include tuberculosis, histoplasmosis, Ecinia salmonella, rheumatologic disorder called Bachette's disease can also look very similar and be tough to distinguish from Crohn's. Within the colon, of course, other infections, um, can present similarly as well as, uh, diverticulitis or uh scabs, so that's segmental colitis associated with diverticulosis. So that's patients who have a little bit of inflammation, uh, kind of in the area of diverticulosis, and sometimes this can be hard to distinguish between IV that, uh, scab and IBD. Um, patients that have cancer and are on immune checkpoint inhibitors, they can develop an IBD-like phenomenon, um, within their intestine, and on occasion we have seen patients who Develop this and it's thought to be immune checkpoint inhibitor and once the immune checkpoint inhibitor is withdrawn, continue to have inflammation and we actually end up diagnosing them with Crohn's or UC. Occasionally colorectal cancer, ischemic colitis, and Kaposi's sarcoma can mimic these, uh, diseases, but hopefully should be distinguishable on biopsy. This is just a picture of scab where we see inflammation in areas of ticks. Um, this is actually, uh, Kaposi, this is a patient of mine who actually had Kaposi's sarcoma, and we, um, initially thought it was Crohn's disease. And lastly, other conditions, NSAIDs, uh, sarcoidosis, vasculitis, uh, radiation enteropathy, lymphoma and amyloidosis. All of these have, um, can present like inflammatory bowel disease, and I've seen several of them. Um, this is the NSAIDs, so this is the IC valve here in the fecal area in the colon, and it's hard to probably distinguish, but there are little ulcers here and this would actually ended up being an NSAID enteropathy rather than Crohn's, but especially because kind of like the terminal ileum and the IC belt area, we, we sometimes get confused. So what kind of testing are we doing for patients when um they present with these symptoms? Of course, colonoscopy is kind of the mainstay of diagnostic testing and IVD. All other tests are, are even colonoscopy too, but um all the tests are supportive of the diagnosis and not necessarily diagnostic. Those include CRP, fecal calprotectin. Uh, and capsule endoscopy which we typically reserve, uh, just in cases where, um, we have not made the diagnosis based on colonoscopy yet. Um, there was a 2015 systematic review that looked at the utility of CRP, ESR, and fecal calprotectin to kind of distinguish between patients with IBS, IBD, and healthy controls. None of the biomarkers um distinguish between IBS and healthy control. However, uh, they showed that patients had a less than 1% chance of having IBD if their CRP was less than 0.5 or the calproductin was less than 40. And so these are very good tests to help rule out IBD when patients present with, um, kind of concerning symptoms like diarrhea, abdominal pain, that sort of thing. This is just um a couple of pictures of uh uh inflammatory bowel disease on colonoscopy. This is a UC patient. This is a Crohn's patient with these deep linear ulcers. Um, the most important thing is we like to document the the severity of inflammation and the distribution wherein the bowel, it, it's located. And then what we're looking for on biopsy is a chronic active colitis or a chronic active ileitis. Um, really, it's having both the chronic and the active inflammation that are, that are, um, key kind of for making a diagnosis. Interestingly enough, we're all kind of taught that granulomas um are found in Crohn's disease and not UC and that is true. However, I would say that we actually see granulomas pretty infrequently on biopsies, even in our established Crohn's patients, um, probably 20% or less of them actually have granulomas on their biopsy. So I just wanna talk a little bit about our um Our, uh, kind of goals in treatment and, um, so what, what we're going for for our patients for treating when we're treating their IBD. So one goal can be clinical response. Um, And uh when patients have a clinical response and that just means that their symptoms improve, that can be associated, of course, with improved symptoms and improved quality of life. If we're looking at clinical remission, meaning that symptoms are completely resolved, no symptoms, that actually has shown to be uh associated with decreased hospitalizations. Um, The and then the kind of the, I guess goal that we're all striving for is deep remission, and that means that their endoscopy is normal, not just their symptoms are normal, but their endoscopy is normal and potentially even their biopsy is normal, and this has been shown to correlate with the avoidance of surgery and minimal to no disability for our patients. And so this is why this is really our goal for every patient is to reach a deep sustained, uh, remission. And um so that we can do our best to avoid surgery and disability for our folks. How do we do this? Uh, traditionally treatment styles kind of started with the mildest, lowest risk medications. However, there is data to support that improve that there are improved outcomes with early aggressive treatment and achievement of remission early. The study showed that patients who went on biologics Early had similar hospitalizations and ER visits to those with actually just mild disease and that the use of biologic was associated with declining resection rates for both UC and Crohn's. And so our 2020 AGA uh UC guidelines suggest using biologic agents early rather than a gradual step up in therapy. So what are the clinical predictors of severe disease? Um, And, and, and, uh, subsequently patients that are at risk for surgery, say patients who are younger when they're diagnosed. Those that are non-smokers, at least for, um, you, this is for UC actually not Crohn's, uh. Disease duration, so having had the disease for a long time, delay in treatment, so, uh, patients that achieved healing of their mucosa at 1 year after diagnosis had a 5 times lower risk of colectomy. Disease severity, of course, so moderate to severe disease versus mild, had a 3 times risk of colectomy. Having had a history of hospitalization. And uh for Crohn's or sorry, for UC particular, having pancolitis, so having um all of their colon involved led to a 20-40% risk of colectomy versus a 2 to 14% risk of colectomy if they only had left side disease. With you see having deep ulcers, high CRPs. And a history of C. diff or CMV infection. Specifically for Crohn's additionally, having penetrating or stricturing disease and perianal disease. So the big, the biggest ones though here are young age at diagnosis, pancolitis, deep ulcers, history of hospitalization and steroid dependence, high CRPs, history of C. diff or CMV infection, and then for Crohn's perianal or fistulizing disease. Those are the patients that are at highest risk of um requiring surgery. To talk a little bit about our meds here. Um, so I broke these down. I'm actually just, actually to fastest onset and, and then we'll talk about the safest ones. So, fastest onset is going to be the anti-TNFs, um, for the most part. We do have multiple options. Uh, some are IV, some are subcutaneous. We have the most data for these drugs because they've been around the longest. They do have high immunogenicity, which means they are high risk for developing antibodies to these drugs that can neutralize the drug and, and make it ineffective. Um, but they are very good for systemic involvement. They, they are systemic immune suppressants and they're really good for other conditions associated with IBD, skin conditions, joint conditions, sorts of things. There is a risk for infection, very, very low lymphoma risk, but not zero, and risk for skin cancers, including melanoma. So, uh, we have our some of our newer drugs, the JAK inhibitors, uh, so GNS kinase inhibitors. These are oral, which is a huge benefit for our patients and not technically a biologic. They're, they're, uh, small molecules and they come in pill form. They have, can have, can have a rapid onset. We have seen patients respond as early as 3 days after starting. Um, they're, they are good for patients who have joint involvement. But there are some safety concerns there as well. There's increased risk of shingles, non-melanoma skin cancers, and actually, um, thromboembolic disease. In fact, there's a black box warning for increased risk of thromboembolic disease, uh, for older patients that are on a high dose of the JAK inhibitor and also have a high risk of, um, or have cardiovascular risk factors, basically. Both of these are are basically essentially contraindicated in pregnancy, um. Though we though we would want the patient to speak with us before stopping them. If they became pregnant. Um, on the bottom, I've included the drugs that have the best safety profile. So, uh, our anti-intecrine is vetolizumab. This is an IV medication. They are testing subQ, though it is not FDA approved yet. Um, this has the slowest, sorry, slowest onset of action, up to 6 months it might take to see an improvement in symptoms. Very low risk for developing antibodies. It is gut selective, which means it's not, um, suppressing the immune system systemically. It's, it's acting at the level of the gut and therefore has a very good safety profile, but it's not great for patients that have other extraintestinal, um, conditions. And then lastly, we have usakinumab and risenkizumab, which is approved for Crohn's only. Um, these drugs are both given with an IV induction dosing and then they're given, um, subcutaneously. They do probably have a little slower onset than anti-TNF, but maybe don't take as long as fetolizumab. They have been shown to be better for anti-TNF failure patients versus vitilizumab. They are low risk for developing antibodies and have a good safety profile and they work really well with the skin. Um, they're, they're really good, for example, psoriasis medications and so, um, there's, these are good for skin involvement too. Just kind of a summary of um I call this our safety pyramid of IBD medications. I think the most important thing to realize is that the least safe thing is inadequate treatment. Let patients keep, uh, kind of languishing away with their IBDs. We do our best to get patients on the most adequate treatment for them. I would say that systemic corticosteroids are, are, again, the, uh, Have, have a high risk for um safety concerns. Um, our thiopurine drugs plus our anti-TNF combos are probably the next least safe, and that's mostly due to the thiopurines. Next would behiopurine upa and Tofaciib. Then our anti-TNFs alone and then our safest drugs I would consider vitallizumab is tikinumab, riseninzumab. OK, so I just wanna spend a little bit of time going through some of the data on uh primary care or general medicine issues for IBD patients. Uh, several studies have shown that patients with IBD actually may receive less preventive health services than general primary care patients, and part of that may be because many IBD patients actually do not have a primary care doctor. Uh, they tend to be younger and often do not have comorbid illnesses and often just see their gastroenterologist as their only physician and, and often don't understand why we're asking them to see a primary care doctor as well. Um, so it's, it's really crucial to clarify with the patient the limits of specialist care and also when they do have a primary care doctor to communicate their needs, uh, to the primary care clinician. More specifically, patients with IVD have been shown to be undervaccinated in several studies. Um, they are at an increased risk for flu, pneumococcal pneumonia, shingles. Um, in this one study of 169 patients, 86% reported current or past immunosuppression use, but only 28% received regular flu shots, 28% had had a hep B vaccine, and almost half basically cited just a lack of awareness of needing these vaccines, um, and being at high risk as the most common reason they did not receive. So what are our vaccine recommendations? Um, all IBD patients, patients, uh, sorry, should receive non-live vaccines that are in accordance with national published guidelines. Some exceptions would be for kind of earlier vaccines. So for patients that are immunosuppressed, they should get the pneumovax, um, or pneumococcal vaccinations, uh, at any time when they're immunosuppressed, and the Shingrix vaccine, we usually recommend at age 50 or older or if they're on tofacitinib, um, or Xeljanz. This is not necessarily a formal recommendation, but it's kind of expert consensus. Live vaccines are contraindicated in patients that are on immunosuppression, and that includes any of these drugs, anti-TNF, oakinab, or Stelara, tofacitinib, prednisone greater than 20 mg a day. Uh, 6 more capturing greater than this dose and then, uh, methotrexate as well, um, at a higher dose. And we would want to wait 3 months after stopping those drugs, uh, before giving a live vaccine. One exception is there is a version of the monkeypox vaccine that's technically live but it's considered non-replicating and that one is OK. We've talked to our infectious disease doctors about that. There's no increased risk of flares with vaccines and um any potential for kind of a reduced response to the vaccine should not discourage vaccination. Um, if a patient is not yet immunosuppressed and but will be soon, um, then we do encourage vaccinating before immunosuppression if possible. So what cancers are patients at high risk for that have IBD? So colon cancer, of course, um, patients are at high risk for colon cancer and we do screen with colonoscopy every 1 to 2 years after they've had colonic disease for 8 years. The one exception is, or one of the exceptions is that we screen immediately, um, not waiting 8 years for patients that are, as soon as they're diagnosed with the concomitant PSC, and they get a colonoscopy every year, uh, strictly, um, annually because the risk for colon cancer is much higher in this group. Patients are at higher risk for skin cancers as well. Non-melanoma skin cancers are increased with azathioprine use. Melanoma may be increased with anti-TNF, and there have been some studies that showed a slight increased risk in melanoma in all IBD patients regardless of anti-TNF use. And so we always recommend our patients, uh, see a dermatologist once a year for skin checks and of course, use sunscreen. Um, IBD patients are at a, may be at a higher risk of cervical cancer, and there is data that suggests that they, the patients that are immunosuppressed might actually be getting screened less, less frequently for cervical cancer. And so we recommend that those that are immunosuppressed, especially if they're on a thiopurine cause that does seem to increase the risk of cervical cancer, that they get an annual Pap smear. Some patients or many of our patients ask about osteoporosis. There is a high rate of osteoporosis in the IBD population, um, probably significantly contributed by, you know, past steroid use, having chronic inflammation, possibly low body mass index, and, um, of course, patients that are smoking. We, in general, we recommend DEXA for kind of national guidelines and then also in patients with particular risk factors, so men that are um that have IBD and greater than 70, postmenopausal women with IBD at age 65, and all, all, um, patients that have risk factors including prolonged steroid use, history of a low trauma fracture, and consider it in, in chronic smokers. I think this would be, this is probably obvious, but we do, uh, of course, encourage tobacco cessation. Um, as I mentioned before, active smoking is a risk factor for, um, more severe Crohn's and reduces response to medications, um, and may increase to, or sorry, may contribute to an increased risk of blood clots which they already are at risk for. Um, we do recognize that active smoking has been shown to actually benefit UC, but of course, we don't recommend it. We still believe patients should, um, Be counseled to quit and offered medical therapy. To do so. If needed. Um, our patients with IBD at increased risk of cardiovascular disease? They are. There was a large retrospective review in the last few years that showed uh heart attack was higher in IVD patients as well as heart failure. It actually showed that getting getting therapy with biologics, so being on therapy for the IBD reduced the cardiovascular incidence rate in this population, so, um, by hazardous ratio of 0.7. And that being on steroids was associated with increased overall mortality over an anti-TNF drug, and so, um, cardiovascular disease and hip fracture were contributed the most to this increased mortality in patients on steroids. So just another reason we wanna get our patients off steroids. Similarly, patients are at higher risk of stroke as well. The, um, risk of stroke was Uh 3% in our Crohn's disease with an odds ratio of 1.54 and 3.4% in UC with an odds ratio of 1.7 as compared to patients with no IBD. And similarly to cardiovascular disease, being on an anti-TNF reduced uh the risk, 0.53 odds ratio and 0.44 um of having a stroke. So treating the inflammation reduced the risk of cardiovascular and cerebrovascular complications. And just to note, we get this question a lot too. Using a daily aspirin did not impact the clinical outcomes in the IBD population in the sense that it did not worsen IBD or cause IBD flares and so we are strongly, we strongly encourage daily aspirin use for patients that are at high risk for, um, Vascular problems. Something that's becoming uh A hotter topic and then people are, are, uh, becoming interested in researching now is the risk for non-alcoholic fatty liver disease in the IBD population. Um, that we do have data that shows that Nafold is higher, or sorry, more common in the IBD population. Uh, and so the blue, the light blue is the general population, and it's actually the highest in Crohn's versus UC. This is NAFfold in general. This is actual NASH, so actual Seattle hepatitis. Numbers are small, but still a little bit higher, and then this is, um, related cirrhosis. So risk factors for Nafoldin and IBD population include older age, higher BMI, longer disease duration, and actually those that have a history of surgical resection had a higher risk for Naffold, which is interesting. Last two slides, uh, so patients with IBD do have higher rates of anxiety and depression. They may have, um, this, and this is associated with increased bowel symptoms, clinical recurrence of IBD, poor response to medical therapy of IBD, poor quality of life, and reduced social support. Um, there was a study that showed that increased depression, there was increased depression and anxiety in patients had a CRP greater than 5. And that um there was in um patients with an active psychcomorbidity and IBD that resulted in 10 excess clinic visits and 3.1 excess hospital days per year. Early recognition and treatment can improve patients' quality of life. And so we recommend that all IBD patients should be screened and treated for depression and anxiety. And last thing, uh, fatigue is another factor that's quite prominent in our IBD patients. This, uh, European study looked at fatigue and its association with work productivity loss of, uh, 1500, almost 1600 patients that were surveyed, uh, it's about 780 returns their surveys. 53 or half of the patients reported some degree of work productivity loss and fatigue here at the top. This was the most common, um, Symptoms cited as work productivity loss. Um, other conditions as that kind of predicted fatigue included the patients that also had arthralgias and active inflammation. So our recommendations for IBD patients that, that kind of complain of fatigue are to screen for nutritional deficiencies, iron panels, B12, vitamin D, uh, often I'll add like a zinc as well, screen for thyroid disorders, screen for sleep disorders, and, um, a mental health screen as well. And then, uh, our kind of recommendations for treatment if all of these things kind of come out normal is a graded exercise program, improving sleep hygiene, um, kind of, uh, mental health interventions like, uh, cognitive behavioral apps, those sort of things. This is our summary, uh, just that, uh, IBD patients do have important general health care needs. We kind of expect the gastroenterologist to perform, of course, appropriate laboratory TB testing for their biologic drugs, perform the colon cancer surveillance. They perform drug monitoring, but, um, at least at UCSF we really encourage patients and their PCP to, uh, work on vaccines, tobacco cessation. Other screenings and um other cancers and depression and anxiety. You can find a healthcare maintenance checklist for your IBD patients at the Chronic Colitis Foundation website. So, uh, thank you, and I'm happy to ask any, or sorry, answer any questions that anybody has.
