During this 20-25 minute pre-recorded lecture, Dr. Abhik Bhattacharya discusses the topic of IBD treatment. 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. Hello everyone. Welcome to the Mount Sinai Board Review course on the treatment of IBD have no disclosures. Let's start with case one. This is a 22 year old male who comes with complaints of eight weeks of intermittent bloody diarrhea. He's having 3 to 4 loose bowel movements a day. No rectal pain. Has my emergency £6 weight loss. Moderate abdominal pain. Does not smoke, does not drink has not taken and sets and works as a researcher at Mount Sinai labs are significant only for mild anemia, stool studies are negative. The flexible sigmoidoscopy shows patchy disease from the rectum to the hepatic lecture. And you diagnosed him as having my left sided ulcerative colitis. What is the best initial treatment approach for this patient? Prescribe oral masala? Mean monotherapy advised that he should be getting I. V. Steroids assessed for latent TB. Have the exposure and starting flicks him up if it's clear prescribed a combo of oral masala. Mean as well as rectal masala. Me and finally treated with a short course of steroids and start vandalism. The correct answer is combo therapy with oral as well as Rector missile. Mean the strike consensus of 28 IBD ologists gave some targets for treatment for ulcerative colitis which included resolution of rectal bleeding, normalization of bowel habits and endoscopic remission defined as Moscow zero or one which was the primary target Histological remission was favored but did not get proposed as a target because of the evolving evidence at that point of time. The sed clinical practice guidelines came up with certain recommendations for assessing severity of U. C. Which includes uh Among the two endoscopic scores which are used in clinical practice. Mayo is the most commonly used and most easily usable scores range from 0-3 with zero being normal and three signifying severe features like spontaneous bleeding and deep ulceration. It is important for us to know disease extent before deciding what kind of treatment we are going to employ for. You see patients can have prostatitis when it's limited to the rectum. If it goes from the rectum all the way up to this planet fracture it is left sided or distill. You see when it crosses the splenic fracture it becomes extensive or pan you see Of note about 46% of patients with prostatitis and 70% of patients with left sided you see can go on to develop extensive or pan you see over their lifetime in this our city patients who got combined oral and rectal Musallam in therapy for left sided, mild to moderate you see did better compared to those patients who got monotherapy with rectal or oral masala. Mean, for extensive you see we again saw that combo therapy with oral and rectal masala. Mean was better than oral masala. Mean for clinical improvement and for clinical remission it was numerically higher but not significant statistically in this our city of masala. Mean refractory mild to moderate. You see patients we found that patients when they were given beautiful night multi matrix therapy did better compared to placebo for both clinical and endoscopic remission composite endpoints based on the current state of evidence. The american College of Gastroenterology recommends for mild prostatitis induced with Director five agents and then for maintenance, continue the same rectal five asA. For any other form of UC which is mild. Start with combo therapy with rectal as well as oral five asa and then once the patient is induced you maintain with oral five asA. Okay, thanks to note there is no dose response when you escalate beyond two g for oral five essay and more than one g per day for rectal five essay. If you do not get response to one formulation of five years, do not switch the formulation. Adherence to daily dozing is comparable to frequent dozing during the day. So you can choose anyone that the patient wants. Except for Procter sigma writers where patients usually prefer once daily dosing and finally rectal five years agents are superior to rectal steroids. Let's go on to the next question. This patient responds to masala. Mean 2.4 g per day. Oral and rectal masala. Mean daily he returns to your office after a year and is feeling well. He is however concerned about the risk of the medication and wants to follow up with you and wants your opinion. What is true regarding the risks of masala me and five years of compounds and how they should be monitored. Number one miss Solomon increases the risk of male infertility and should consider switching the five years. A compound patients should have families and libraries checked yearly. Number three patients should have Hizb U. N. And creatinine checked yearly. The patient should switch to self a solution if they are worried about developing nausea and finally disease flare while on five years of therapy are never due to the drug themselves. Yeah, the correct answer is the patient should have the Burin and creating and checked yearly. This slide shows some of the commonly encounter side effects and uh patients who are using five years of therapy now five years agents also have some peculiar side effects. About 30% of patients are sensitive to the self a mighty seen in self isolation and they can get symptoms like nausea, vomiting, diarrhea and rashes. Um sometimes you can get this interesting paradoxical worsening of colitis on patients who are being treated in the Solomon and five years is if these symptoms continue or get worse, you may even have to consider discontinuing this five S agent. There is a risk of interstitial nephritis with 5S agents. It is uncommon and occurs usually within the first year of therapy. We need to be cautious when patients have pre existing renal conditions. Hence the FDA now recommends monitoring the view and creating at least annually, went on five years of therapy. We'll go through a couple of scenarios for the same patient. Number one scenario patient is in remission for a year and decides to take the oral medications 2 to 3 times a week instead of daily. He returns from a family vacation and suddenly has severe onset of symptoms, including 8 to 9 bowel movements a day and nocturnal stools, weight loss. He's anne make has high crp stool studies he different negative flex. It shows me or to colitis and path shows chronic active colitis throughout you decide to start the patient on inflicts a map to which he responds well and shows endoscopic improvement. He's on the infliction man for three years but starts losing response at the end of three years with 78 bowel movements a day. Weight loss, increased urgency. Again, he has leukocyte, Asus anemia, high fecal cal protecting drug levels look fine and still studies are negative. What do you want to do next? Would you increase the infliction up to 10 mics per k. Switch to a dilemma maps, which to us taking a map, switch to vandalism map or refer the patient for collecting me. The correct answer is switched to stick in a man In the gemini induction study, we found that better perform better than placebo in moderate to severe ulcerative colitis for clinical response. Clinical remission as well as mucosal healing. Even in the maintenance faced video performed better than placebo for clinical remission at 52 weeks as well as Mucosal remission at 52 weeks in the landmark varsity trials comparing veterans a mob and add aluminum head to head. We found that for clinical remission vandalism have overall did better compared to a dilemma. But when we subdivided by TNF exposed patient, they did not seem to have any difference in outcomes. Similarly for endoscopic improvement better than the mob did better compared to a dilemma mob overall but not in the TNF exposed group in the unified trial used to kinda mob did better than placebo for primary outcomes for moderate to severe ulcerative colitis in the induction phase. Even in the maintenance phase used to get a map perform better than possible for moderate to severe ulcerative colitis. So the eight year treatment guidelines that came out this year for moderate to severe ulcerative colitis say the following for induction we can use systemic steroids. Anti TNF federalism abuse to kinda map as well as sofa set up for maintenance. We can use to hyperion as monotherapy. Anti TNF federalism abuse to kinda map or two for Sydney. The treatment guidelines also suggest that only for moderate you see you can induce and maintain with five monotherapy as well as builders and multi matrix therapy. However we have to know there is no role of methotrexate monotherapy and you see no role for five years as an adjunct treatment of patients have already failed therapy with five S. Is no role of tire period monotherapy and induction. But there is some role in maintenance, no role of systemic steroids and maintenance. If biologic naive inflicts a mob and vandalism map should be your first line agents and in case they are exposed to anti TNF agents used sofa and sticking of them above other agent. Now let's go to the second scenario. Patient has been in remission for about a year on masala. Mean and decides to take the oil medications every 2 to 3 days instead of daily returns from a vacation and found found to have severe symptoms. He's having 12 bowel movements a day. All the marquis asia multiple nocturnal stool, £10 weight loss. You decide to send him to the his heart rate 120 beats per minute. He's tachycardic. He has slightly low blood pressure, he has Lucas psychosis. Anemia. Crp is high, low albumin stool studies are negative. You do a flex IQ which shows severe ulcerative colitis in the rectum and path confirms your findings. You admit him to the hospital. Start him on I. V. Solemn adroll 20 mg every eight hours after three days. There is no improvement in symptoms and crp is only mildly improved. What is your next step? Send patients for origin collecting me start him on I. V. Infusion of solemn model and continue for two more days. You can start him on I. V. Cyclosporin and transition to therapy in video as a maintenance therapy. Start inflicting my rescue therapy or start vandalism of rescue therapy. The answer is D start inflicting my rescue therapy in this patient with acute severe and severe of collide at the end of three days. You need to be able to tell whether the patient is responding to steroids or not. There is an 85% failure rate at day three. If the patient is having more than eight bowel movements a day or has a crp of more than 45. Similarly if the album is less than three or if the patient has colonic dilatation, then there is an 85% chance of failure of steroids. So we need to decide quickly what we need to do at this point of time. So patients who are hospitalized for severe ulcerative colitis first start an I. V. Steroids at data to assess the response. If they're not responding, you need to put them on netflix a map or cyclosporin rescue therapy. If they're not responding to the medical therapy, you proceed towards surgery at any point of time during this stage. If the patient develops perforation, toxic mega colon or hemorrhagic colitis, you need to stop any form of treatment and proceed directly to surgery. There is no rule for a dilemma mob. Golimumab or vandalism mob in these patients to a certain if there is no role. However there was a small case series that came out of michigan using 10 mg t idea with some favorable outcomes. But this is not ready for primetime. Stay tuned fecal microbiota transplantation also does not have any role in this scenario, the size of trial compared cycloSPORINE to inflict the mob. In the context of acute severe ulcerative colitis, There was no difference between cyclosporin and inflicts a mob. In terms of treatment failure rates at the end of the study period at 98 days. If you do end up using cyclosporin, please keep in mind a few things. No one make sure that the patient has a maintenance therapy option, Make sure patients on PCP prophylaxis, maintain cholesterol about 1 20 as well as normal serum magnesium to reduce seizures. Uh make sure that the patient has got renal function. If there is a rising creatinine by more than 30% reduced to those immediately. Uh To mix up a cake is as effective as for mix pancake and does not have the same amount of toxicity and finally cyclosporin level should be checked and adjusted appropriately. Despite the initial response to inflict the map, the patient starts losing response over a period of time. Uh He starts having more diarrhea and now he doesn't want to do any kind of uh ivy or injection therapy and wants to go for an oral therapy. So you decide you want to do a set name and uh what do you want to tell the patient about Sydney. The risk of herpes. Zoster is similar between two opposite knee band placebo so far is a selective jak inhibitor and blood council unlikely to be affected non melanoma skin cancers are not increased on sofa and sofa may not be used as first line therapy as opposed to anti TNF for you see. So the answer is, D Tofas should not be used as a first line therapy for mild, moderate to severe you see, as opposed to anti TNF. This light shows that the risk of hope is those two compared to placebo. From all the trials as well as open label extension is higher photo of a certain it was compared to placebo. The risk does go up as the age progresses. If the patient has priority and a failure or if the patient. Ization other adverse events that we need to be aware of. Our nasopharynx. Itis are tragedia and headaches. LDL HDL cholesterol as well as creating kindness do seem to increase with so far. But we don't know what the clinical significance is. Non melanoma. Skin cancer does increase the two of us at night. So if you're starting a patient on a certain level, you need to make sure that you check the cbc at baseline at eight weeks and then every three months lipids don't need to be checked at the baseline but can be checked at 4 to 8 weeks and if they're normal, do not check them again. Liver enzymes can be checked every few months like 3 to 6 months and any abnormality should be investigated further from the rheumatoid arthritis trials. We found that patients who are on top of that never had a higher propensity to get blood clots uh including both P. S. And D. V. T. S. But when we looked at our own data from all the trials that we have done, only about five patients developed any form of uh VTS on uh of a certain age. And all these patients were on the high dose as well as had risk factors for VT. So if you do have patients onto of a certain, we do need to talk to them about this and uh we need to de escalate therapy from 10 mg to five mg as soon as possible. Despite these patients initial response, he began requiring higher doses and eventually re hospitalized with severe symptoms during hospitals here and goes a sub total collector me and three state J pouch formation. Six months following Julius thomas closure. The patient reports having 8 to 12 bowel movements a day denies joint pains, fevers or rectal bleeding, this is ah the pouch body which shows bronchitis patient is treated with ciprofloxacin and his symptoms improved. But after stopping the therapy for one month, his symptoms recall what is the next best treatment start empirical predniSONE for Crohn's disease. Start empirical Cipro with probiotic for presumed pouch itis order apart program to rule out pouch prolapse and prescribed low motel for irritable bowel syndrome. The answer is start empirical ciprofloxacin with via cell number three for presumed bronchitis. So far pouch you need to treat them with two weeks of antibiotics when they get the first uh episode of pancreatitis. If they respond to antibiotics, you ah treat them with the same antibiotics but also give probiotics. If they become dependent on antibiotics, you make sure that you give them on chronic low dose antibiotics along with probiotics. If they do not respond to antibiotics, make sure that you give them a full because of combination antibiotics and maybe uh look at the culture and sensitivity. Uh if they respond, put them on chronic low dose antibiotics along with probiotics. If they don't, you can start them on steroids, immuno modulators or biologics. Make sure you exclude other causes like Australia, Meskhi, mia, C. M. V. And Crohn's. Other things to consider in pouch are things like our fighters, which is uh information of the rectal cuff groans of the pouch. Um strictures, ischemia, irritable pouch and sphincter damage secondary to surgery leading to fecal incontinence. And now for something completely different, let's start talking about Crohn's disease, which of the following is true about combo therapy with infliction. Robin immuno modulators than Crohn's disease combo inflicts a mob and is a therapy is more effective than is that happening alone steroids. methotrexate and inflicts. The map together are more effective than steroids and inflicts. The mob in active Crohn's disease, immuno modulators have not been shown to decrease formation of antibodies to a dilemma mob and methotrexate is more effective than is a therapy in in combination therapy with anti TNF. So the correct answer is combo therapy will then fix them up and he's a therapy is more effective than he's a therapy in alone. Mhm. I'm sure everybody is aware of the landmark sonic trial. Uh In this uh immuno suppression, naive patients were treated with chemotherapy and compared to monotherapy with inflicts. A mob was his monotherapy with is a therapy and were found to have better steroid free remission at the end of 26 weeks when they were on combo therapy in this next question, which of the following is not true about federalism map in treating Crohn's disease. Federalism A was shown to be effective in achieving clinical remission but not response at week six in patients with priority and have treatment, higher rates of remission and response are seen at 10 weeks but not six weeks as compared to placebo. Vandalism A was not shown to increase the risk of infections except for nasopharynx itis. And finally, oral cholera vaccine is effective when patients are being treated with federalism and the correct answer is d oral cholera vaccine is actually not effective when patients are being treated with federalism. In the induction phase of the Gemini two trials, we found that widowed performed better than placebo at six weeks for clinical remission but not for response During the maintenance phase of them. Gemini to trial. We again saw that video did better than placebo at 52 weeks for all outcomes, including remission CD 100 response as well as steroid free remission. But when we looked at patients who had undergone TNF failure, we saw that video did better than placebo only at week 10 but not earlier at week six. Battle is a mob is a gut selective agent. Innovates mucosal immune responses. So oral cholera vaccine responses can be blunted but a hepatitis B vaccine is not affected. Nasopharynx itis increases significantly when compared to placebo. And so far we have not seen a single PML case when patients have been treated with metal is a mob following a switch to a dilemma mob combination therapy along with that happening this patient response for a few months and then lose his response. A really mob drug levels are detectable with no antibodies. There is active disease seen on colonoscopy and M. R. E. And the decision is switched to made to switch tools to kinda map in advising the patient about was taking my with statement is true. Number one patient does not require latent TB testing prior to therapy was taking a map induction. Those in his way dependent as compared to anti TNF was taking a map has no risk of immunogenicity. Was taking a map is only approved for Crohn's disease as it is not efficacious and ulcerative colitis. So the correct answer is that was taking a map conduction does is very dependent in the unity studies of Crohn's disease. We saw that you stick in a map performed better than placebo for clinical response as well as remission for all its doses In the maintenance phase was taking Web did better than placebo at week 52 for all outcomes including clinical remission clinical response as well as steroid free remission. A 20 year old male comes to you with mild to moderate illegal Crohn's disease and it's prescribed six mp. At 1.5 mg per kilograms per day. The PMT activity was normal. You review potential side effects of the medication and recommend monitoring. What testing do you advise to the patient in two weeks. Number one, check a complete blood count and differential check families and light pace check abdominal ultrasound, check a quarter Farran or check chest X ray. The correct answer is check a cbc and differential thai opinions are known to cause a pretty significant side effects which can range from G. I. Symptoms of para toxicity pancreatitis which can be uh pretty idiosyncratic lymphoma infections as well as some patients just do not tolerate the medication interestingly. Milo suppression is only seen during the early phases and is much lesser during later stages of therapy. So if you're starting patients on fire period. You need to check for TPM T if it's low, you do not treat them with hyperion's if its intermediate treat them at half doors. Monitor for Cbc every week for a month. Then every two weeks for two months and then every month thereafter if they're normal TPM T start them on full dose X. M. P. And is that or is that european monitored the cbc every two weeks for first two months and then every three months thereafter. LFTs can be monitored every 3 to 6 months for patients who are on fire puritans. Coming to the next question, which of the following statements is true regarding malignancy, risk of medical therapy for Crohn's disease. The risk of lymphoma in patients treated with chemotherapy of anti TNF entire appearances, 20 but 10,000 patients per year patients treated with hyperion's remain at increased risk for lymphoma indefinitely. After stopping therapy, Risk of non melanoma and melanoma. Skin cancers are high in combination therapy. When compared to monotherapy with anti TNF risk of melanoma is increased in patients treated with higher pureeing but not increase in patients treated with anti TNF, the correct answer is c the risk of both melanoma and non melanoma skin cancers are higher in combination therapy. When compared to monotherapy with anti TNF, this slide shows the higher relative risk of melanoma as well as non melanoma skin cancers on patients on combo therapy as compared to monotherapy with anti TNF. Even the risk of serious infection than opportunistic infections are higher on combination therapy as opposed to monotherapy with anti TNF. So what is the risk of developing northern Hodgkin's lymphoma in patients on immunosuppressants. If patients do not receive any therapy, the risk is too and 10,000. If they receive some kind of immuno suppression, the risk goes up 5-8 and 10,000. So it is numerically higher but still not that high. Next question, a 39 year old woman with Crohn's disease who's been treated when you fix a mob monotherapy for the last 12 months at five mics per kig every eight weeks comes to you for follow up. She's noticing that for the last infusion cycle she starts having Increased symptoms two weeks before her infusion. Which of the following statements is true. There is no utility in measuring anti drug antibodies or trough levels. In this situation, antibodies to inflict the mob are not likely to be present. Since the highest prevalence is during the induction phase, patient presents loss of response to inflict them up. Therefore, switch to different therapeutic class is the right choice at this point, shortening the infusion interval or increasing the doors is likely to improve her response and switching to a dilemma is unlikely to alleviate her symptoms. The correct answer is d shortening the infusion interval or increasing the doors is likely to help with her symptoms. Now let's look at the next question with deals with a similar concept. The patient responds to the shortening of interval of the inflicts a map to every six weeks. However, six months later she starts noticing increased symptoms. Diarrhea abdominal pain. You obtain labs and you find that her crp is elevated C. Diff is negative. You order drug levels and find that inflicts a map is undetectable and antibodies to inflict some elaborate high titles. DP empty activity is normal. What is the best approach and management? You switch to more a dilemma monotherapy, switch to a dilemma mob combo therapy along with his Ethiopian, increase the dose of infliction up to 10 mics per cake. And also add is Ethiopian switch to federalism at monotherapy or continue the same dose of infliction mob but just add steroids. The correct answer is b switched to a dilemma combo therapy with his Ethiopian. Whenever a patient is losing response to medication, you need to make sure that the patient has active disease. If they have active disease, look at their drug levels if they are low and there's low antibody levels, you increase the dose of the medication. If they have low drug levels with high antibody levels, you need to make a switch within class. If they have low drug levels and low antibody levels, you can add an immuno modulator to get more bang for your buck and if they have adequate drug levels and low antibody levels. You switch out of class. Now let's look at post operative Crohn's disease. A 42 year old woman who just had her first a little section for small bowel obstruction from structuring, claims that this comes to you for follow up uh before her surgery. She was on his art therapy in and now she's considering medical therapy to prevent recurrence or what should you recommend to these patients? Generally? Time for recurrence is not influenced by a disease behavior, smoking reduction does not reduce the risk of recurrence. And this topic records at 6 to 12 months after surgery can predict clinical records the effect of inflicts a mob or Carolina mob in prevention of post op preference has not been studied prospectively. The correct answer is C endoscopic records at 6 to 12 months can predict clinical recurrence later in life. The idea came out with a technical review of post op Crohn's disease guidelines and the dichotomies patient based on factors into low risk and high risk. Low risk were older patients. Non smokers had the first surgery for a short segment fibers genetic disease and had longer disease duration, High risk for younger patients. Smokers two or more soldiers for penetrating disease. With or without the absence of ah periodontal disease. And these patients were at higher risk of having endoscopic records in the new terminal ilium endoscopic records in the new terminal ilium can be scored on this scale called the root killed score and patients who have I zero or I wan have 10% risk of endoscopic records in one year. And score of more than I too can have more than 90% endoscopic records in one year. The cut off point from I want to I two is presence of five or more apt is also in the new terminal ilium. This is something that we all need to be aware of. The poker trials showed that the endoscopic guided treatment in the post operative period for Crohn's disease had better outcomes than compared to profile active treatment. The absolute risk reduction for endoscopic as well as clinical recurrence at the end of two years was significant for both. Low risk as well as high risk post operative patients. Which argues to the point that both low risk as well as high risk patients should be monitored aggressively during the post operative period with the help of colonoscopy. This was another major trial which looked at inflicts a map profile Actiq treatment and patients who underwent illogical reception and found that there was no difference in clinical reference at the end of the trial period, so it did not meet its primary outcome. However, it did see that endoscopic recurrence was much lower in patients who were on profile active conflicts among both surgery compared to those who were on placebo. Now, This is important because we know that patients have endoscopic disease much before clinical disease. It takes at least 3-5 years to pay for patients post operatively to get clinical disease. But endoscopic disease can be present as early as a few weeks. This slide summarizes all the treatments discussed in the presentation so far With this, we come to an end of the presentation. I hope you enjoyed the presentation and good luck for your boat. Thank you.