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Histologic Healing in Inflammatory Bowel Disease

Feb 26 | 12:30 PM

Inflammatory bowel disease (IBD) is an umbrella term used to describe disorders that involves Ulcerative Colitis and Crohn's Disease. What is histologic healing in IBD? What treatment protocols to be followed and investigations involved? Does histopathology makes any difference? Learn about the revolutionary concept of healing in IBD by joining best GI panel of India.

[Music] of gastroenterology at kfc mangalore we have dr partha pal who is consultant gastroenterologist at the aig hospital hyderabad and then we have dr anuradha see karen who is a hrd of pathology at aig hospital hyderabad so today we'll know what it is uh you know in inflammatory bowel disease does a histopathology make any difference and uh the concept of histological healing and how to achieve that histological remission so with that uh i would welcome dr partha bhal to start off with the slides thank you everyone thank you for the kind introduction so i would just set the perspective for today's discussion that why this histological remission or complete revision is required both in amsterdam politics and as well as in crohn's disease so discuss that i'll discuss two case scenarios the first one is of our 20 year old 28 year old female who was an ideal professional she had a 12 month history of pain abdomen and roots tools i have colonoscopy short terminal ulcers as you can see in the insect with colonic ulcers with skip areas city and programming showed only terminal ideal involvement no other small vowel involvement he received she received uh antiperspirant therapy in the past which was ineffective for six months but this biopsy was suggestive of bronze disease then later on after six months of therapy with azure therapy those optimization according to her body weight there was no pain abdomen has boosted she gained weight uh she was planning to go abroad since uh hence a colonoscopy was repeated but isioscopy showed persistent ulcers so at that time to achieve clinical endoscopic remission we started her on an aluminum map with azure therapy therapy and after three months as you can see the ideoscope is showing complete endoscopic remission and she is maintained now on other adolescent and other maintenance biomarkers are also normal like crp and pickle gal protecting that means deep remission is achieved that both clinical emission endoscopic remission as well as the biomarkers are normal this is called deep remission so she wants to know her future risks of relapse surgery pregnancy rates etc as she was planning to marry and go abroad anything else can be done in this case so uh actually current evidence is actually showing that you can assess transmural healing not in this case but in other cases like you have small bowel involvement or in the deep small vowel in those cases uh if there is skip area then these are present you can assess actually trans neural healing because we know that cross disease is a transmutable disease so this is this picture is from the systematic review that was published last year in landsat gastroenterology which is showing that um this mrna before and after treatment optimization after the treatment there is a complete transmural response as well rather than only clinical and endoscopic emission so why this is important uh this is important because if you achieve transmural healing this is a paper from which was published in elementary pharmacology and therapeutics we showed that the steroid emission rate the clinical relapse rates are lower need for hospitalization on surgery are lower if you achieve this trans neural healing also recently paper was published in cgh and last year which showed uh the importance of assessing cross-sectional imaging uh in case of post-operative recurrence in crons there is not only endoscopic mucosal heating this transmural healing may be important in these cases and this study has shown that who are having both endoscopic remission as well as radiological transferal healing they have lesser chance of relapse in future so how to assess transparent healing after starting a new therapy you can do a power ultrasound after 12 weeks and see if the bowel wall thickness is less than three millimeter with a doppler and other vascularization parameters and after 36 weeks you can actually do a mr intrography or ctn program to see for the bible sequences reduced to normal that is less than 3mm and there is no contrast enhancement and no complications like abscess picture and picture this is how we define uh trans mural healing so uh this is actually the window period of early disease in case of crohn's disease uh if there is we treat the patient uh before the complications developed by stricture fistula or a surgery occurs before that we diagnose then the risk of this complication are lower so what is this early disease this is actually from the disease onset to diagnosis from the diagnosis if we this initial 18 months is the actually called this early disease according to the paris definition there is no such criteria for early alternative colitis but usually uh that there can be fibrosis and long-term uh sequel so uh there also also ulcerative colitis the main difference from cross is a mucosal disease rather than a transferable disease so but i will discuss that later also so this because 18 months is important because early disease in this case we diagnose the patient early within 12 months although the patient received therapy with anti-tubercular agents this is our paper that we published earlier in elementary pharmacology and therapeutics in 2018 and uh we have shown uh if the patient receives antibiotic therapy the risk of this complications like picturing complications of surgery are increased and if the diagnostic delay is more than 18 months actually uh the strict chain complications are 2.5 times higher and surgical complications are four times higher so uh that's why we have understood the importance of transmural healing and early his diagnosis and treatment next case the case of ulcerative colitis the 30 year old male with a new case of acidic colitis came to me actually it was a pancolitis and steroid dependent disease here's history of azure induced pancreatitis so the affordability issues for conventional biological anti-dna or values map so it was started on two first significant induction 10 energy twice a day on with five aces and asked to follow up 28 weeks so after induction therapy came for follow-up school was two per day and there was no blood so this is according to the definition he actually clinical emission but should we taper too far not to five mp twice a day at this point so we did a colonoscopy this is actually not the same case scenario but in patients who are maintained and achieving endoscopic remission uh with a clinical emission for a stable period of six months with opacity name only if there is neo endoscopic subscore is zero or there is no anti-dna prior anti-dna fuse in those cases you can actually uh taper that the positive goes from 10 mgb to 5mdb without increasing the risk of collapse but if there is minimal endoscopic activity as well that may increase the risk of relapse in future so in that question conclude that and later on after he achieved the stable dimension we referred those to 5mg to abd he also wanted to know future risk of relapse so can the doctor do anything else because already complete because the leading is there so colonoscopy we've taken biopsy from different segments he was worried why again biopsy was taken because already endoscopic healing is present that could be important because this is the concept of histological remission this is the systematic review that was published in gastroenterology in 2020 which showed this mayo endoscopic subscript that is endoscopic remission is achieved the chances of relapse is low and also furthermore going a step ahead if you achieve histological remission with endoscopic remission then the chances of relapse cardia is only five percent so uc is also progressive disease although there is no such paris criteria for early ulcerative colitis but in long run it can cause also stricture pseudopolyps uh then fibrosis dismodility and incontinence and later on can cause colorectal neoplasia and even after surgery 30 percent of the patients may still be symptomatic because of house related complications and this is another paper uh that i discussed in my earlier talk uh that this paper showed actually this uh last year it was published that in periodic ulcerative colitis which long-standing disease actually causes fibrosis and there is uh fibrosis and the muscularis propria as well as muscularized mucosa as well and the bowel wall thickness is increased so this is the current stride to consensus the short term targets are symptomatic response that the patient responds clinically the intermediate targets are deep remission that is endoscopic remission as well as biochemical remission and long term responses are improving quality of life and absence of disability and these are the optional choices but this may be important in future where there is transmutable healing that we discussed and also histological ending for ulcerative colitis uh do these biologics alter the natural history of inflammatory disease so uh this is my last slide so this is actually our abstract that we have submitted for echo this year this show that after uh patients are on uh stable dimension that is clinical as well as endoscopic remission if you stop biologics the chances of recurrence uh relapse in future is less if rather than if the patient stops when the pressure is not on both endoscopic and clinical remission so with this i am uh passing the response to the next speaker just to set the perspective for transferable healing in france and the histological dimension in ulcerative colitis thank you dr partha i will be talking about mucosal healing in ibd both ulcerative colitis and crohn's disease now mucosal healing is a very important step in the cheat to target approach of ibd so i'll be concentrating on that only so in 2021 this stride to proposal for cheat to target approach was published in gastroenterology both for crohn's disease as well as for ulcerative colitis the target for crohn's disease include clinical response clinical remission biochemic biomarker normalization endoscopic healing the new one quality of life and disability and transmural healing is not a target as such but it's an adjective measure so now clinical response is assessed by what is known as patient-related outcomes in the case of crohn's disease it includes abdominal pain and loose bowel movements now if these are reduced by more than 50 in two weeks time we say that patient has clinically responded on the other hand clinical remission is much stricter target and takes much more time so therefore it's an intermediate target both clinical response as well as clinical remission are not the long-term goal the long-term goal has to be something more that is endoscopic healing biomarker normalization again takes some time and it's an intermediate target the two biomarkers which are usually evaluated are crp as well as fecal cal protected the crp should be below the norm uh upper level of the normal and this is the the fecal calc protecting should range anywhere between 100 to 250. now endoscopic healing is an important long-term target and it takes time the healing of the mucosa takes time therefore it has to be a long term healing and but if you are not able to achieve the endoscopic healing then you need to strategize your treatment maybe you should escalate your treatment a new treatment target has been the change in quality of life and disability all these patients suffer from poor quality of life especially if the disease is active now if you have achieved an endoscopic healing you achieved a biomarker normalization but the quality of life of the patient has not improved then that patient will not be satisfied so nowadays is an added target and quite often you will find that the quality of life improvement may not go hand in hand with the other markers of optimum inflammation so that is a separate entity altogether and has to be included as a therapeutic target lastly dr partha talked about transverse yielding now trans mural healing requires some sort of cross-sectional imaging maybe mr entrography ct andrography and more recently the small bowel ultrasound now transmitter healing is a much more difficult target to achieve and the present available treatment has very low rates of transparent healing so therefore has not been added as a therapeutic target i will be concentrating only on endoscopic healing how do we achieve that how successful are we in achieving endoscopic healing so firstly the crohn's disease now mucosal healing processes generally consist of absence of ulceration the ulcers which are present in your initial endoscopy should deal completely now that is the art stick which has to be used and it's been defined as restoration of normal mucosal appearance by endoscopy of a previously inflamed region and the complete absence of ulceration in some studies they have also included even the erosions also should go away with or without histological signs of inflammation that histological healing should be there or not will be discussed later when you are comparing mucosal healing data across trial you need to take several factors into consideration it may depend upon the definition which was used in that trial was it based on objective scores such as simple endoscopic score or crohn's disease endoscopic index of severity or just merely presence or absence of pulsation what was the study design was it re-randomization of the induction responders was dose optimization allowed or not what was the study population type what was it bio-9 where you will find that the results are much better or included significant number of entities in the failures what was the disease severity of the population what was the disease duration longer the disease duration more difficult it is to heal the mucosa now comparison across child takes into consideration how much healing was measured and defined most of the trials would use some objective scores such as simple endoscopic score or crohn's disease endoscopic index of cbrt but the earlier trials included they just showed whether or not mucosal ulceration is present and and the the event is simple endoscopic so the cutoff for mucosal healing has been different many have taken equal to a less than four most many trials have taken equal to a less than three but the more recent trial is stressing on stricter criteria that is the simple endoscopic score should be two or less and that was what was used in acoustic enemy app trial called as unity im trial but most trash nowadays use simple endoscopic score which is a practical and simple alternative to crohn's disease endoscopic index subsidy it has four variables size of pulses ulcerated surface the affected surface and presence of narrowing and you got points 0 1 2 3 for each variable and these changes have to be noted in five vowel segments distal ileum right colon transverse colon left colon and sigma colon and rectum the total score may range from 0 to 56 the endoscope healing would be considered if the score is less than 3 now i move on to the the success of biological therapy in achieving mucosal how good are they in achieving mucosal healing you know that the biological agents are the best agent to induce nuclear building and that was shown by sonic track the first biological therapy which was used in ibd was anti-tnf therapy starting with infliximab then ada was added so what was the success rate of mucosal healing in the fixed map trial accent one trial both in the lows of 5 milligram per kg or 10 milligram kg per kg the the mucosal healing at week 54 was between 46 to 53 percent roughly half of the patient achieved the living in adelaide map the extent trial the mucosal healing was 24 as compared to zero percent in placebo but this was a trend which included roughly half of them were previously exposed to an ttnf agent in fixing map so this success rate was not that good most recently a series cd trial was done in which conventional therapy was compared with therapy based on therapeutic drug monitoring and the endoscopic healing was assessed and they found this endoscopic response can be seen about 45 percent of patient and the endoscopic healing or remission occurs in about one third of patients so both uh entity enough therapy that that eliminable and infliximab can achieve your portal hearing the sticking map is is a monoclonal antibody against the p40 subunit of interleukin 12 and 23 and has been found to be useful for both prones as well as for ulcerative colitis the maintenance trial of your sticky map known as immunity showed that the endoscopic response occurs in about 24 percent and the mucosal healing is much lower around 17 percent the success and achievement of living at week 44 was not that great but many of these patients were actually having severe crohn's disease with the acscd mean score was 15.4 and 44 percent were actually a gnf alpha agent entity and of refractory patients stardust study compared the tree to target approach standard of care approach forest in map and they found that the endoscopic response can be seen in about 37 and 29 percent and the mucosal reading in about 14 to 16 percent video is map is a gut selective monoclonal antibody against alpha 4 beta 7 integral and it prevents the trafficking of lymphocyte into the gut mucosa and that has been found to be useful for both elasticity colitis and prone's disease versus if i study evaluated vitalism in in crohn's disease they had a mixed population some were anti-teen of naive and some were anti-tnf exposed or paleo patient the overall response the pop of the population was 54 which was pretty good and the mucosal healing could be achieved in about 18 the results were much better in patients who are anti-tnf9 where you get an endoscopic response in almost two-thirds and the mucosal healing is about 25 on the other hand if the patient were entity in a failure the mucosal healing was pretty poor about eight percent uh this was a trial which was performed with widower's map in refractory and antigen of refractive population so difficult to treat corporations the 88 percent were anticipating of refractory and the endoscopic outcomes were assessed at week 26 and week 52 and they found that the endoscopic remission happened in about 33 and 36 percent at week 26 and 52 respectively response was a little bit better 40 and 45 so you saw that most of the biological agents will induce some sort of remission but the mucosal healing but generally the rates will vary between 30 to 50 percent the healing of the bowel in different segment might be different may not be uniform for example this was a analysis of the data from extend trial which i talked about uh earlier of adulthood in crohn's disease and they found that the the bowel healing was better in rectum sigmoid colon and left colon and transverse colon as compared to right colon and ileum so bowel healing might be different in different vowel segments another trial showing the same that the distal item the healing was the worst whereas in the transverse colon and the the ascending colon and the left column much better lastly the versify study which i talked about and that also it was found that the ideal healing was poor whereas the transverse colon ascending the colon healing was the best so when you're planning your biological therapy you need to take into consideration what type of crohn's disease the patient is having predominantly eyelid disease or freedom in colonial generally the eyelid disease is more difficult to treat moving on to the endoscopic healing and ulcerative colitis now most of the trials have used mayo endoscopy substore for for assessing the cbrt of the mucosal disease score zero would indicate a normal mucosa where you can see the vascular pattern nicely whereas the my disease includes erythema decreased vascular pattern and mild probability moderate disease would include market erythema definite probability absent vascular pattern and erosions are also considered as score two score three includes ulcers depulses and spontaneous bleeding now like in crohn's disease even in ulcerative colitis different er sticks have been used to define mucosal healing most of the trials have used endoscopy subscore of zero and one as dr pata showed in his slides that there is difference between endoscopic subscore 0 and 1 and more recent most recent trial which will go in a jack inhibitor has been used mayo endoscopic subscore of 0 to define mucosal region which is much more difficult target than male 1 scopic we all know that they are excellent in in the treatment of ulcerative colitis the initial trial was known as one trial and five milligram per kg or 10 milligram per kg and frequency map induced mucosal healing in about 45 percent at week 54. ultra two trial was the trial with adelmi map here that almost 40 to 50 patients were or had already received an entity in a patient and the healing the mucosal healing was much poorer as compared to in fixing my 25 [Music] the placebo healing rate was 15.4 uh more recently a serine uc trial was performed where three dosage regime of adeline was used either at 40 milligram every week or every other week which is the standard dosage or at a given on a therapeutic drug monitoring regime they found that the mucosal healing or because the healing response was similar across all the dosage scheduled between 41 to 51 percent now this is the visible one child which [Music] compared the the newer formulation of uterus map subcutaneous formulation with iv formulation the substituted formulation was given 108 milligram every other week and the standard iv vitulism formulation was given the dosage schedule of 300 milligrams at zero two and six weeks and 300 milligram every eight weeks and they found that the mucosal healing can be achieved in more than fifty percent it was a secondary endpoint in the original gemini child the mucosa healing with widow was more than fifty percent so it is excellent agent to to heal mucosa in ulcerative colitis you see varsity trial was a trial which compared widow with adolescents in achieving mucosal healing in ulcerative colitis so they again had anti-change of naive population as well as entity in a failure population the overall response showed that the mucosal dealing was much better with widow 39.7 as compared to edda which was 27.7 delta was about 12 percent and it was significantly statistically significant the results with the video was much better with anti-tnf navy patient where you could get mucosal healing in 43 percent whereas with data it was 29.5 again the difference was significant but if the patient had ex has been exposed to ntt patient earlier or for the failure with entities of therapy the mucosal healing was significantly less lastly tofacidna also has been shown to be a useful agent in the treatment of ulcerative colitis and just now partha showed excellent result in a crohn's disease but in ulcerative colitis results are much better and the mucosal healing at week 52 which five milligram videos 37.4 and 10 milligram video it is 45.7 which is much significantly better than placebo i will pass on to dr anuraga so thank you sir so before we move on uh just to have a couple of questions on the previous topic of endoscopic healing so in uh we have seen the studies and uh two cases so uh sir just to know in real uh in clinical practice what kind of scores or do we have we have seen from the trials but in the practice any scores that are being used uh like you have sacd and myo subscribe practice which one is usually used to practice yeah i mean i do use endoscopic support for all ulcerative colitis patients and i've been using that for a long period of time as far as crohn's disease is concerned i have started using simple endoscopic score for last two or three years so that way it is better and it's more objective as compared to the previously where i used to say that extensive ulceration appeared to have decreased as compared to the previous endoscopy so those statements are a little more subjective now if we can actually calculate and much better and we use we have pasted that simple endoscopy subscore in our we also use this ulcerative polarities in uh telescoping in uhd as well yes for the endoscopic yeah that is also an alternative okay so follow-up question is sir you had mentioned about your echo paper on uh you know tapering down or stopping biologics once endoscopic remission is established so uh in in in your practice have you seen that you know uh stopping the biologics after a certain period of time has there been a you know relapse of the disease once the endoscopic remission is achieved and the biological system uh [Music] can you repeat that yeah so in the echo paper that you had recently presented where is prevented so to what percentages have you seen that the relapse has been prevented so this is actually only a comparison of our registry that [Music] clinical remission as well as endoscopic remission if the patient stops the chances of endurance is less and whenever the patient is already on remission stabilization for more than one year the chances of recurrence is even less on in those cases and because there are lot of reasons for biologic discontinuation in our this one we cannot stop it in a controlled manner because of cost uh infection and many other causes patients stop biologists and also between in between orbit also many patients could not come to the hospital and stop biologics so [Music] there is no such a strategy but we actually try to do that whenever these patients are in clinical endoscopic clinician also in some patients who are non fistulizing disease because in visualizing disease strong's the chance of recurrence is very high and also the steroid dependent patients uh these are the patients in which this recurrent states would be low that is some other analysis on our paper we have seen that this the hazard ratio for recurrence in facializing problems is very high so only we try in uh non-fictionalizing transgender who is in a stable clinical as well as endoscopic remission this can be a triad actually and also uh the recurrence this even after two years 33 percent only relapsed others did not so that's why we gave the title of our paper whether this severe disease that is whether this changes the naturalist of the disease or not that needs to be seen in prospective trials but that was the observation for a long-term registry okay thank you so we'll move on to the next set of slides i'd like to welcome dr andradam good evening so am i audible yes yes ma'am you are awesome today i will be talking on what is the role of histopathology in the diagnosis of ibd and not in the diagnosis but in according to the current guidelines what role it plays in uh following up of these patients so if you see that for an accurate diagnosis of uc on histology the minimum requirements which are a must are the clinical details the duration of the disease the age of the patient and type of the treatment because many times the patient would have received treatment elsewhere and would have presented to your c i think there's a network problem uh we'll just wait for her the diagnostic accuracy because the picture uh um the normal biopsies when they are well oriented they are like your test tubes so the crips reach on to the mucosal surface which is said to be normal so when we are trying to say that there is ibd we look at the architectural changes which is the first point which gives us an indication whether there is any chronic changes so the first picture shows your normal colonic mucosa where all the crypts are like parallel test tubes reaching onto the muscularis mucosa and if you see the second picture you have the crypt distortion you have increased space among the crypts you have basal lymphoplasma cytosis and you have the panic cell metaplasia and pyloric gland metaplasia crypt atrophy is when the crypts are shortened and they do not reach up to the muscularis mucosa and this is a very important point which indicates a trophy and this can start as early as seven days post involvement crypt branching and crypt budding are also features of chronicity laminar propria inflammation is where we try to assist the amount of inflammation whether it is mild moderate or severe and the type of inflammation whether there is no fills and neutrophils which i will tell you in the in the consecutive various scoring so how do we assess these important parameters and activity is when you have intra epithelial inflammation that is the neutrophils which is called cryptitis or your luminal correction of the cells which is the crypt axis so the stride um two as dr tantri has already covered the latest guidelines currently the stride two says that histological healing can be used as an adjective measure for the endoscopic in addition to the end endoscopic healing and the histological healing is the trick to target approach in the uc in various studies so as we see in 2015 histopathology was considered as a sensitive measurement of inflammation but it was not considered as a trick to target because we didn't have enough evidence and enough clinical utility in 2019 and 2020 various studies have shown that histological remission can be used as a target for remission in uc and can be considered as a target for treatment in ulcerative colitis and accumulating evidence indicates that microscopic activity persist in endoscopically quickened ulcerative colitis and histological changes usually lag behind clinical remission even after treatment and many studies have shown that absence of histological activity will predict a lower rate of relapse decreased hospitalization decreased surgery and subsequently decreased neoplasia now the if you see this one study of histological activity this was a prospective multi-center study of asymptomatic patients who were in endoscopic remission and undergoing clear surveillance colonoscopy so if you see the first figure with mayo score of endoscopic score of zero still 13 percent had active uh disease and with those who had mayo endoscopic score of one 43 percent had active disease so even 12 months after the index endoscopy 23 percent experience c and nancy index should be zero and giga should be less than two for defining this historical remission and the main and the minimum requirement are the total absence of intraoptical neutrophils erosion and ulceration so if you see that when we talk about persistent active inflammation there is mucosal atrophy with complete loss of crypts and there is expansion of your laminar propria by marked inflammation with acute inflammatory cells that is neutrophils and basal plasma cytosis in particular the basal plasma cytosis indicates a frequency of relapse and when we talk about quick colitis or chronic inactive colitis that means we are saying that yes they are architectural changes but they are minimal and they can be loss of parallelism or branching when we say mild architectural changes and they can be financial metaphors here but what is most important is there is no evidence of neutrophilic infiltration the indicators of relapse on histology are presence of basal plasma cytosis mucin depletion that is there will be total loss of goblet cells there will be increased activity kryptitis or kryptopsis and they will be increased neutrophils and eosinophils in the laminar propria so to for example this is a patient who is a female patient 29 years a known case of ulcerative colitis was presented with high grade fever bleeding correcting increased frequency of bowel movements and abdominal pain for 10 days colonoscopy showed pancolitis with complete obliteration of vascular pattern granularity and friability with a ucei score of 5x8 so usually this biopsies are done to know the activity and also to look for any viral inclusions so whenever we get a biopsy of a follow-up patient it is very important that we look for any relapse features or any persistent activity or any evidence of neoplasia or viral inclusions so this particular patient had marked erosion or ulceration which according to nancy's will be a direct score for and if you see in the ulcerated areas you have enlarged cells with amphophylic cytoplasm and intra nuclear vacuolations and these are the cytomegaloviral inclusions which are located in the ulcerated area and you can use immunohistochemistry with cmb antibody and those dark brown dots which you are seeing are the cmv viruses which are highlighted with the inc so this was a young patient who had a cmv superimposed infection now just to give a brief on the various histological indices that we use the jivo scale is empirically very well developed but it is complex but this uses seven parameters the first is the architectural changes or the second is the chronic inflammatory infiltrate third the laminar property are neutrophils and eosinophils and the crypt destruction and then the grade five that is erosions or ulcerations each are given a score of three except for erosions or ulcerations which are scored four so you can have a score ranging from zero to five point four and five point four is the highest score which indicates a more severe historical information this has high levels of intra-rater reliability but very not that strong inter rated reliability the robot system pathology index is a refined version of the jivo's grading scale and this has used four reliable jibos indices that is the chronic inflammatory infantry lamina proprio neutrophils presence of neutrophils in the crypt epithelium and erosions or ulcerations and each are given a score of 0 to 3 so that you can get a total score of 33 and a score of less than 6 is considered to be remission the nancy's histological index is a most simplified easy to use adaptation of the gebo scale and this uses three historical items and grade four is the one where you have ulceration and presence of ulceration is a direct grade four and grade one you have chronic inflammation but absence of acute inflammatory cells grade two is mildly active and grade 3 is moderately active disease so the worst feature determines the final score so histological features below the highest grade are not captured now since we have so many indices it is always better that you use one of these indices to have a common agreement with your gastroenterologist on what is the activity you over a period of time is always better to evaluate rather than using a single score as a predictor of neoplasia particularly in the long term follow-up of patients now different studies have used different histological outcomes in the various clinical trials uh over the years and they have found that some have used gbo score and some have used nancy's course it's very difficult to compare different trials because the criteria for inflammation and activity are inconsistent and the study designs are different so let us see one study of histological remission in patients with anti-tnf nav uc patients who were treated with infliximab or adeline here if you see the the both the week 52 with inflexi map 50 percent of patients had clinical remission 55 percent had mucosal healing but surprisingly 35 percent had histological remission only when compared to adeline who had 26.5 percent of remission all in in these cases the mayo score was used for clinical remission of less than two for mucosal healing mayo endoscopic score of less than one was followed and histological remission give a score of less than three was used and this showed that infliximab showed a much better histological remission than adeline in this population of patients uh another study with ustekinumab in ulcerative colitis here the few of the patients were on placebo and a few patients were nostrils in your back 90 milligrams subcutaneously for 12 weeks and fewer or 90 milligrams eight weekly and here the parameters which were taken to assess the histological improvement were that you should have less than five percent of neutrophils in the epithelium absolutely no crypt destruction there should be no erosions or ulcerations and there should be no granulation tissues and this australis bank was found to be more effective than the placebo and at 90 milligrams eighth weekly showed a more uh much better histological remission when compared to the other dose of 20. the vile city studied uh which show which was done for uh uc which had a study duration of 52 weeks and um there were two arms of patience and each arm of the patient received at least one dose of either adeluma or um that is 40 milligrams for every two weeks or they received vidulism for 300 milligrams and the baseline histological disease activity was evaluated and in these patients it was uh found that vidolimap treated patients had higher rates of structural revolution at 52 weeks and they had higher rates of minimal histological disease activity at 52 weeks and also they had higher rates of histological remission plus endoscopic improvement at week 52 the verdict study which was used to evaluate the optimal target in uc we there were three uh target groups and in group one the end point was only for treatment to symptoms group 2 was treatment of symptoms plus endoscopic remission and group 3 was treatment to symptoms endoscopic remission as well as histological activity and the primary endpoint in all the three uh groups were to follow up at 96 weeks and these were the patients with moderate to severe ulcerative colitis and if these were correlated with the biomarker sampling it was found that the and uh that patients who had these uh increased fecal biomarkers uh had less of clinical remission and less of mucosal healing the biomarkers which were evaluated were cal protection lactoferrin and hemoglobin and uh it was shown that lower levels of fecal calprotectin correlated very well with histological remission patients with elevated fecal lactoferrin were those who were having more active historical inflammation but the exact thresholds could not be validated and c-reactive protein could not be used and it's not advisable to use as a surrogate for historical activity but there's still a lot of unresolved issues in historical scoring of disease activity one is because you have to give at least two to three months for the patient on therapy before we think of assessing historical remission on biopsies early histogram measurements are however still useful because they give you information regarding the effectiveness and may predict the treatment response at a later time point an early detection of historical response definitely gives an indication on the therapeutic efficacy and absence of response at the early point could suggest that probably the patient is resistant to therapy and therefore we can always switch on to another agent instead of continuing the patient on this subway how the colon and ileum heal during the therapy is not certain because the healing rates at the colon and in the ielium were differing in different studies so this requires much more studies to uh to see which response earlier so the current treatment target goal in uc is not only symptom remission endoscopic healing and histological healing but probably still molecular healing to think of a total depth of remission coming to crohn's disease in crohn's disease in addition to the chronicity features and active features which we have seen in ulcerative colitis there is another parameter which we need to assess which can be seen in a few in few percentage of patients and that is the granulomas these granulomas are usually small osteocytic aggregates of around five histiocytes these are microgranulomas located mainly in the lamina propria and whenever you have large confluent necrotizing granulomas and disproportionate submucosal inflammation and granulomas above and below the mucosa or granulomas in the ulcerative areas the most common differential diagnosis in our country would be to first rule out a cox rather than considering a crohn's so as we said the brand lumas and crohn's disease are found only in three percent to 82 percent and that too after very very diligent search and usually they are more common in children and also they are more common in um in patients who are on long term steroids or who have received biologics or have received immunomodulators or who have multiple hospital hospitalizations usually we find more granulomas in those subset of patients than the knee patients and also the granulomas are more common in the digital column and rectum but sometimes you can also find in the stomach and eyeliner and it's not a necessary point for your diagnosis but if found can be of an important marker so the eco guidelines on crohn's disease states that lack of historical activity in an endoscopic biopsy may not reflect inactivity or remission in crohn's disease because crohn's as we know is it can extend beyond the reach of the endoscope and what we are evaluating could only be the mucosal aspect of it so the biopsy of crohn's disease may not be representative of disease activity and as dr khan said so you need to check on the transmitter check on the recovery of the transmural inflammation through your mre or through your ct endography basal plasma cytosis eosinophils and granulomas are not recommended as markers of histological activity or historical remission for crohn's and epithelial granulomas should not be considered as a marker of histological activity but you can use it as a prognostic marker because i said that grand lomas are more common patients who are received much more treatment and the scoring system which is used for evaluating these romance disease unlike the uc is the global histological activity score and this is the colin global historical activity score as well as the ideal global historical activity score but this lacks formal validation studies and the nancy's histological index can therefore be used even for crohn's disease biopsies in clinical practice because it's very simple and easy to use the definition of histological remission for crohn's and is a very stringent definition and that is normalization of the mucosal histology with complete absence of erosion ulceration no evidence of epithelial damage complete absence of intrapatellar neutrophils and lack of any sort of increased inflammation in the laminar property so the stripe two which proposal of treat to target approach in crohn's disease uh does not include the histological healing but considers the transmural healing as one of the adjunctive measures so this is not endorsed as a formal new treatment target yet so if you see the transmural healing and is gaining recognition as a treatment goal currently in crohn's disease and why should we target transmural healing in crohn's disease because the trans crohn's when it affects the entire length of the mucosa it leads to thickening of the bowel wall narrowing of the lumen and as the disease progresses there can be deep ulceration structures fistulas abscesses and so this requires a full thickness biopsies which is which cannot be done uh in a follow-up of a patient uh who's on treatment obviously so these are a few pictures to show patients who had to undergo surgery who did not respond to treatment and you can see that their the first picture shows the skip lesions the mucosal irregularity and nodularity the second picture shows the ulcerations and the cobblestoning effect the third picture shows the fat creeping the microscopic pictures below show the crypt architectural distortion granulomas in the laminar proprio and transmural inflammation with lymphoid aggregates and one classic sign which we see is the lymphatic aggregates hugging the serosa which is called the rosary sign and there is fat creeping on so but still the treatment goal in chrome's disease is from transmural healing the concept of histological healing is catching up unlike the molecular healing of ulcerative colitis so histological improvement was definitely demonstrated in several studies who were on conventional and biological therapy in crohn's disease who were on inflexible single dose and maintenance dose and several studies have shown that there was a decrease from the activity as much as 8.3 to 3.4 and they have used the global historical activity disease scoring so histological healing is more strongly associated with clinical outcome in high level crohn's disease than endoscopic healing and the prognostic value of histology in patients with crohn's disease restricted to ileum has shown that histological remission is definitely associated with the clinical relapse free survival and reduced need for any medical escalation or corticosteroids and the level of agreement between the endoscopic activity and historical activity was fair at 63 percent and microscopic inflammation persisted in 36 percent of those with endoscopic healing so in patients with crohn's restricted to terminal ileum there is definitely the potential of considering astrological healing as a prognostic marker because this has shown to have good clinical outcomes and this is exactly the same paper which shows that the follow-up on the histological remission and historical activity in the study so another drug which showed vidalism have induced historical response in refractory crohn's disease patients and they have shown that when it was compared between week 26 and week 52 so the uh in patients with baseline colonic global uh global histological activity score was greater than four and there was definitely a remission of uh patients of um around 20.5 percent in poland when compared to the islam of 34.3 and there were absence of neutrophils in the primary and the sub study populations which was a very important point of historical remission so just to show a case this is a 27 year old male a follow patient of crohn's disease status post ic resection who had to uh come now complains of stools of two per day with no mucus or blood a colonoscopy show clean based ulcers with edema around the anastomotic side biopsies were taken from the anastomotic side to look for any recurrence of the disease and this is the biopsy which we have got there were focal superficial mucosal erosions and uh there was mild dis architecture in this array and if you see there is some basal inflammation in the lamina propria they were lymphoid aggregates not only in the mucosa but also in the submucosa with thickening and spraying of the muscularis mucosa which indicates that there was narrowing there and um there was scripted disarray with areas of crypt loss and cryptotrophy and there was activity in the form of interactive neutrophils and there was increase in the laminar proper inflammation of neutrophils as well as eosinophils so this but we could not demonstrate any ulceration as evident on the endoscopic findings so if you take a nancy's astrological index this was around grade 2 and there were no viral inclusions so this indicates possibility of a recurrence of the crohn's disease at the anesthetic side so your biopsy can give a clue about the activity recurrence absence of neoplasia and absence of viral inclusions i have one last case do you want me to show that uh yes so this is a 14 year old boy who presented with abdominal pain low grade fever and weight loss since two and a half years there was a history that his maternal grandmother has just recovered from pulmonary tuberculosis hemoglobin was around 10 gram person esr was normal 10 mm albumin was 3.5 and his chest x-ray was normal his ct showed enlarged miscentric lymph nodes and mild hepatosplenomegaly a colonoscopy was done which showed ideal nodularity and the rest of the colon was normal bmft showed fixed distal regional looks with thickened mecentric margin and there were segments of narrowing and dilatation in the allele loops so this is the colonoscopy ilioscopy which only showed iel nodularity and so an ideal mucosal biopsy was taken which was non-specific however the tissue sent for mpb pcr stain positive so the patient was started on anti-tubercular treatment five weeks post att the child still presented with persistent symptoms so because of this a decision was taken to evaluate the child further and a diagnostic lack was done and liver and small intestine were normal there was a situs minimalist multiple miscentric nodes were there one of the nodes was taken for histopathological evaluation it showed granulomas but they were non caseiating so because there were granulomas in the centric lymph node the patient was continued further on att and the patients responded there was weight gain there was less of symptoms and then post 10 months he again came back and he was readmitted because he had pain abdomen he had scrotal post discharge with fistulous openings at the perineal and root of the scrotum ct showed persistent miscentric notes and fluid collection in pelvis and a repeat diagnostic lab now showed one foot of distal jejunum which was grossly thickened bubble wall was thickened there was thickened mesentery there was fat creeping and multiple enlarged lymph nodes which was in contrast to the previous diagnostic lab where there were not much of all these findings so a full thickness small bowel biopsy was taken and the perianal biopsies were also taken the perianal biopsy showed a granulomas afp was negative and this is the full thickness biopsy which showed chronicity in the general mucosal villi were blunted and there were granulomas which were transmural and you can see that they were it is breaching the muscularis mucosin present even in the submucosa and there is a fissure like ulcer which is extending into the submucosa submucosa showed muscularization of the of the submucosa and these are granulomas in the muscularis propria and the granulomas were cuffed by lymphoid aggregates there was no necrosis so and uh mecentric nodal biopsy also showed granulomas afp negative so this was the case of a crohn's which was masquerading as cox so we have to know the subtle points that you can have crohn's miscentric nodes showing randomers um but most of the cases of ibd may not have eccentric nodes showing randlomas and it's a dictum that cox usually shows granulomas both in your mucous as well as in your nodes and before we label a child is early ibd uh maybe there are other parameters which need to be evaluated because this child initially presented only thank you thank you ma'am and thank you how to capture the proper ipt diagnosis so uh with that uh maybe i can have a couple of questions here uh in terms of uh you know what is the if we would like to know what would be the biopsy protocol for uh [Music] from india as well from cmc below that if you take a segmental biopsies from all of the parts in this tank like i lium secum then assembly colon all the parts and that increases the there is incremental increase in the diagnostic yield if you take even from the normal areas uh you can take all the segments the incrementally diagnostic yield impressions of transition specifically for bronzers to differentiate from tuberculosis the segmental bias is very important because even if normal area if there is architectural distortion that goes more in favor of crohn's disease i think mam can give more ideas some right on that yeah so um we recommend and we have seen that um in our institute we usually get segmented biopsies uh properly labeled and submitted in different areas so wherever there is um no endoscopically no activity we have found microscopic foci of involvement which is a very very important clue for evaluation of this crohn's disease but clearly if you take the upper gi involvement in crohn's like your gastric and deodorant biopsies the only indicator to say that there is involvement of crohn's disease in stomach or deodorant is for looking at focally areas of enhanced gastritis which is an isolated area of involvement by inflammation of your lamina proper neutrophils and ears nucleus so as we said normal mucosa should not have any active neutrophils so when you have a presence of neutrophils or increased eosinophils it indicates um according to these jivo's orange and other scores it indicates activity and also we have found that you can have microgranulomas which are in the areas of endoscopic areas so definitely i would um say that we should take multiple biopsies from different uh segments and this will definitely increase the yield um and improve the diagnosis as also another point was earlier uc was thought to be only a rectal predominant and sparing the upper gear but now it is no longer the fact and we know that the ulcerative colitis can also involve the upper areas so this is where evaluation of the multiple areas will help us and particularly in pediatric age group esophageal and gastric involvement are much more common again we have multiple scoring systems so in your practice phone with school would you prefer usually uh nancy yeah so i think nancy is very useful and easy to adapt and between it reduces inter and inter observer errors between the pathologists so um and it's a scoring of only four parameters so nancy would be the ideal to use for both ir you see as well as stones and finally for transmural healing in in the clinical practice how often does it use the parameter of transmitter sir you can [Music] so yeah so already i've shown in my slide that after uh say for example if you're given the therapy for more than six months then you can access for the transporter hidden by either a city andrography or [Music] and there is no features of complications like fistula or abscess if that is present then this transporter has been said to be present my only problem with assessing this transparent reading is a very low sort of success so i do not know suppose you have you have a patient who is on inflexible and you're doing well is clinically responded within clinical remission endoscopically you find no ulcers would like change if there is a histologically active disease or else the the analytrography [Music] [Music] we also worry about side effects and toxicity

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dr. BV Tantry

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Professor, Department of Gastroenterolog | KMC, Mangalore

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Director & Chief of Pathology | AIG Hospitals & Asian Institute of Gastroenterology, Hyderabad

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Consultant Gastroenterologist | Asian Institute of Gastroenterology

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Dr. BV Tantry

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Dr. Anuradha Sekaran

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