Chapters Transcript Video How I Practice Now: Positioning Therapies for Crohn's Disease Dr. Singh explains a 4-step approach to picking the right drug for the right patient. Our next speaker is Dr said Sing. Um he is a gastroenterologist and assistant professor in the department of medicine at the University of California san Diego. Um and he will be talking about talking to us about positioning therapies for Crohn's disease. Thank you so much and thank you Bruce for that wonderful clock. There is clearly an art to this, but at the same time I think there is some scope for mass personalization of therapist to a certain degree in terms of trying to bring everybody up to the same speed. Yeah. Uh these are my disclosures over the last two years. Um and this is my overall approach and the outline of this talk is a four step approach to picking the right drug for the right patient, recognizing that we're probably going to be right. Only half the time. We'll talk about the concept of balancing patients, risk of disease complications with the efficacy of these therapies and minimizing those complications. We'll talk about the patient's risk of treatment related complications and contextualize that with a competitive safety of therapies. Now, I round out with aspects related to predicting response to specific agents. And at the end of it put it all together, I talked briefly about my approach to laura Crohn's disease and subsequently high risk Crohn's disease. Um so this is a broad conceptual model that I talk about with patients and that's how I think about them. Every patient has an intrinsic disease risk as to what is the likelihood of them getting into trouble because of their disease and on top of that, what we are trying to do in our clinical practices, balance the treatments, intrinsic, efficacy and safety, as well as the patient's risk of treatment. In trying to choose the best medication and the overall goals are very similar. We want to achieve sustained remission, minimize the risk of disease complications and surgery while at the same time avoiding the risk of treatment complications and infections. At the end of the day, we want our patients to have a full life without any disability related to disease. Yeah. So let's take a deeper dive into what our patients risk of disease complications. And how do we think about it in Crohn's disease Bruce mentioned this uh, talking about historically, we focus on disease activity of patients, which largely represents a cross sectional assessment of the inflammatory, important symptoms, signs and endoscopy, largely assessing how the patient is doing today. However, what is increasingly important and I think we all recognize this over a period of time and our practices that what's most important is the longitudinal disease course and historical factors that provide a more complete picture of the prognosis and overall burden of disease. So, we're trying to figure out how a patient has done historically and how that influences our decisions are treatment decisions to improve the longitudinal outcomes of our patients. So, in that regard, I IBD came up with an overall assessment of disease severity and in a way to assess assigned patients as high risk Crohn's disease or low risk Crohn's disease? And this is based on the burden of structural damage, inflammatory burden and impact of the disease on quality of life who were while somebody with high risk Crohn's disease will have large or deep mucosal lesions, presence of peri, anal fistulas or abscesses. Prior intestinal resection is particularly long seven intersections strictures and have extensive disease leader, pan colitis or extensive illegal disease, high c reactive protein, low help human And the disease would have significant impact on quality of life. More than 10 loose bowel movements, lack of symptomatic improvement with prior exposure to biologics. Ottoman suppressive agents and overall life limiting disease. Um in contrast, somebody with lotus disease may have after so smart, superficial ulcers without any of the disease complications, officially abscesses or strict. There's no prior surgeries, limited short segment anatomical involvement without this significant impact on biomarkers. The disease may have a modest impact on daily activities without disease related hospitalization and largely may have absented Miley active symptoms. Right, I will now focus the rest of my conversation primarily surrounding high risk Crohn's disease because that's the more difficult to treat disease and that's where most of our data are. Um and in the end I have summarised what my approach to lower Crohn's disease is. So what do we know about the competitive efficacy of different therapies for preventing disease related complications. Uh putting all of the available therapies at this point for christmas disease together in a single slide in biologic naive patients. The yellow represents the placebo arm and what has been the national placebo rates for most of these medications. And it's even clinical remission and this outlines all these trials on the same side. And like Bruce mentioned there multiple different approaches, especially in the absence of head to head trials. But even in the presence of head to head trials are network meta analysis can be used to inform treatments. So traditionally we think about pair wise meta analysis is basically comparing to drugs that have been compared head to head. Uh so we are adequately able to inform whether drug one is more effective than drug to business in traditional Paraguay's meta analysis. Network meta analysis on the other hand, combines both direct evidence from head to head trials, as well as indirect evidence which may be born out of a common competitor in the field of diabetes. Historically it has been most trucks being compared to placebo. And we inform on the indirect relationship, for example, between drug one and drug three which have not been compared head to head with each other. But both of them here have been compared to drug too. So we inferred in a probabilistic relationship between Drug one and drug three. Mhm. So what if we apply the concept of a network meta analysis to moderate to severe Crohn's disease. This was a recent update based on available data from recent is a map that bill shared uh a more comprehensive network to a significant extent because there are some head to trial. They represent data and later, more recently published on you stupid remembers aluminum ab and some data comparing combination therapy between therapy unions and anti TNF agents versus anti TNF monotherapy. So if you look at first line therapy or what we call biologic naive patients in moderate with moderate to severe chronic disease, what we basically see again, drawing your attention to the blue part here, which basically assigns all of these medications against each other in a complex network to a certain what is their relative efficacy for inducing clinical remission. And if you just follow the role and compare it to the column treatment for example, inflicts map has 6.2 times higher odds of achieving clinical remission as compared to placebo. And similarly, if you go across the board, we can compare a rule to a particular column. The things that stood out here more consistently are inflicts map combination therapy of inflicts have entire appearance at aluminum ab used to can map all of them were more effective than certainly is a map a goal for inducing clinical remission. It is important to note that even in the primary trials of socialism. Epic goal, it did not meet the primary endpoint of clinical remission. And this medication is actually not approved in europe and Canada it is available in the United States with an FDA label which focuses on its ability to maintain clinical response and clinical remission. Mhm. Uh putting it in the context of relative efficacy through something called a sucre. The ranking of these agents through a hypothetical turning. And even in the concept of network meta analysis, what we generally see is that a combination of inflicts nominees othello print is probably our most effective agent here we are looking at the black bars for inducing clinical remission and the dotted lines here talking about maintenance of clinical remission. So if you just look at the black bars, inflicts map and add aluminum are probably our most effective agents. You're stuck in the map subsequently follows along with that I think is a map after that. Um, talking about second line therapy and patients have had prior exposure to anti TNF agents here again, in the current context is limited head to head data. We also were largely relying on indirect comparisons and if you look at indirect comparisons as Bill had alluded to in stock, looking at the efficacy of I'll 23 antagonists or racing cars and the magnets context. We generally tend to see that right sank is a map tends to perform better than vandalism app overall, most of these agents are more effective than placebo except perhaps very ill. Is a map in this comparison through network meta analysis. But if you look at other agents, right sank is a map and add aluminum tend to out from vandalism map a note here about a dilemma mob. Again, it's primarily been studied in patients who had either immunogenicity to inflict some ab or intolerance. It does not include a patient population that have primary non response to inflict map. You do induction therapy with inflicts a map and a patient does not have any response to that medication at all. Um Ahmad has just not been studied in that patient population. However, if you look at a group of patients who had a prior response to inflict maB and subsequently last response potentially due to immunogenicity or intolerance. Adenoma mob is a very good alternative in that situation. We don't clearly see things getting out and comparing that sank his members is used to get a map here. But again, recognize that this is in direct comparisons for a smaller group of patients who are anti TNF refractory. So somebody had to have trials that are coming along will probably provide more evidence. Um following a similar approach of uh ranking these agents at aluminum tends to perform well here. Now we are looking at the solid gray line for in the production of clinical commissioning biological exposed patients. But again, like I said, adam ab applies to a smaller group of patients whereas broadly speaking used to can have and raise secondary Thank you. Zainab Tend to outperform some of the other agents. As 2nd 9 agents and somebody with prior failure of anti TNF agents. So what we're clinical guidelines from the A. C. A recommend this published earlier this year and what they say is that an adult out patients with moderate to severe Crohn's disease who are naive to biologics. The A. G recommends the use of inflicts map at aluminum or used to kinda map Uber socialism at Eagle. This is a strong recommendation based on moderate certainty of evidence. In contrast, based primarily on indirect comparison and the effect size. The easiest suggests the use of vandalism over socialism at Tegel. This is a conditional recommendation with lower certainty of evidence. But again, most of these agents tend to perform better than certain is um My pagan. In contrast, if we start looking at patients who've never responded to TNF antagonist patients with primary non response in that situation, the A. G recommends the use of use chicken a map over no treatment and being a strong recommendation. And it suggests the use of vandalism map as an alternative treatment option in the absence of any other treatment, as a conditional recommendation. In contrast, if you look at a subgroup of patients who have had previous response to inflict some have been subsequently had loss of response in that situation, The eight year recommends either the use of add aluminum or used to command over no treatment. A small counters if at aluminum and was the first line drug that was utilized and indirect evidence would suggest The option of using inflicts amount is a 2nd 9 agent. Now, the guidelines in this situation again suggests the use of vandalism about well no treatment as an alternative treatment option. Um This is a pivotal headwear trial that was recently presented by Bruce um at the DW the civil trial which was comparing used to kinda map versus adenoma map for moderate to severe Crohn's disease. First headwear trials are very commendable and what we basically saw in this trial is that patients were randomized to either standard those of you stupid. A mob with a double dummy design for placebo subcutaneous injections versus added in an amount of wood and the placebo ivy. And subsequently, with standard of care patients were followed out two week 56 to assess the primary endpoint And what was essentially a primary endpoint of week 52, what was essentially observed is a complete overlapping the rates of achieving clinical remission and week 52 in a group of naive patients with a dilemma for use it in a mob to both of these agents were similarly effective in achieving clinical remission. The rates of response over a period of time and the speed of response was rather compatible and similar. I'm not sure that this was designed as a non inferiority trial, in which case it would not have met his primary endpoint. If this was designed as a superiority trial, then it shows that you're stuck on a map is not superior to add aluminum but just looking at the data, it seems rather comparable to add aluminum app released within reason from each other. What do we know about? We talked about you, sick animals being a potentially a preferred option in patients with primary non response to anti TNF agents. More so over vandalism ab. So while there is positive clinical trials in that realm, especially head to head trials, there's plenty of observational data coming from europe and other countries which is looking at through different methodologies of observation of comparative effectiveness research trying to compare you Superman versus federalism ab in a subset of patients with Crohn's disease with prior failure of anti enough. This is one such study, 130 patients comparing these two agents and what they essentially observed in this observational study that used to be in the map is a superior to vandalism ab in achieving particle studio clinical remission as well as biochemical commission in this patient population. These findings have subsequently been replicated and at least three or four other observational studies. So consistently saying that in anti TNF refractory patients used to in America is probably a better regent as compared to vandalism. Yeah, so summarizing this part, we can identify patients at high risk of disease complications, busy and structural damage, inflammatory burden and the overall impact on quality of life in general for most patients with moderate to severe, prone to these TNF antagonist, particularly inflicts weapon at aluminum ab may be the most effective first line agents used to kinda map may be the most effective second nine agents, especially in a subset of patients with primary non response to anti TNF agents. Moving on to the aspect of patients, risk of treatment complications and competitive safety of therapies. The two most important factors that go into choosing the therapy are largely the efficacy of an asian and its safety. So conventional wisdom suggests that this is a sample of the pyramid of safety of these different therapies. TNF antagonists in combination are probably um carry the greatest risk of serious infections and complications to for sitting. It probably fits right in. There may be worse than TNF antagonist based in recent safety warnings. You stick in a map is a very safe alternative and vandalism and monotherapy by virtue of its got selectivity probably has a superior overall safety profile. However, what I want is to think about is what are the risk factors too serious and opportunistic infections. Um This is data for for TNF agents from large clinical trials. So, Adelina map data close to 242,300 petaluma matt treated patients um and the risk factors for serious infections of pretty consistently in moderate to severe disease activity and the use of cortical steroids. Um the treat registry for inflicts map again, risk factors for serious infection is a baseline moderate to severe disease activity using our products and predniSONE and inflicts that by itself also increases the risk of serious infections. But what I do want to point out is it's just not the agent in isolation that's been used to treat the disease, but other factors including underlying disease or activity and the need for cortical steroids are associated with an increase in the risk of infections. This is data from the treat registry. Thinking about what were the types of serious infections that were observed in patients with Crohn's disease? And here, what is important to know that a lot of these serious infections were actually inter abdominal infections of pelvic infections, which could potentially be deemed to be more disease related infections. Says that an inadequate disease control is probably a key risk factors to see these infections uh in patients with Crohn's disease. Um and we've seen it ourselves. Well, there is a time dependent the risk of serious infections. This was a study that we did comparing anti TNF agents to federalism. Ab PMF agents in blue and vandalism at an orange and as we see, the proportion of serious infections over time tends to change. A similar study from Denmark, saying that the risk of serious infections of Antique enough agents as compared to immuno modulators, probably highest in the 1st 3-6 months and subsequently the risk declines. So Overall, of serious infections tend to occur within 3-6 months of fresh starting immunosuppressive therapy and this risk progressively declines over time. So I would suggest that there are two key factors that influence the safety of the therapy. One of them is the intrinsic systemic immune suppression potential of therapy were good selectivity of certain agents or lesser immune suppressive potential of other agents may be attractive, but at the same time, treatment effectiveness and controlling disease is equally important, especially in modifying the short term risk of serious infections. Uh we try to contextualize this. Looking at the risk of serious infections between anti TNF. Asians versus battle is um having patients with diabetes e in a real world observational study. Um and here if we compare vandalism after Pff agonists, looking at all serious infections, extra intestinal serious infections and which may not be disease related. We versus gastrointestinal serious infections which may be this is related at least for christmas disease. We see a clear pattern we know and recognize as Bruce show that for ulcerative colitis um inflicts them up and it's very similar to vandalism and terrorism may be more effective than a dilemma mob. So if the effectiveness and controlling diseases similar vandalism, Abba is safe where is compared to anti TNF agents for ulcerative colitis. However, I want to bring your attention to the Crohn's disease lying here there. It does not seem to be any safety advantage advantage of vandalism have worse is the NFL for antagonist for patients with Crohn's disease in particular if we start looking at gi serious infections. In fact the risk of gi serious infections including CDF and other enteric infections. Besides intra abdominal abscesses, the risk is higher with federalism as compared to anti TNF agents and this was not just a one off study. Uh same issue of the clinical gastroenterology and hepatology. Very similarly designed study comparing anti TNF versus vandalism app across all of these groups. And here again if we look specifically at ulcerative colitis, vandalism up seems to have a lower risk of serious infections but that safety advantage that we think about does not seem to be the case for Crohn's disease says that there is no difference in the risk of serious infections. How do we contextual used to can amount within this concept. So we created a multi center electronic health record based with industry of all liability patients are seen within the U. C. System across if I use this as well as cedar Sinai. Um And in this analysis again preliminary data um there seems to be a suggestion that used to can amount perhaps as a low risk of serious infections as compared to TNF agents in blue and vandalism app in orange here and we confirm some of the prior observations for risk factors to serious infections but if we do a multi variable analysis used to kinda map may be associated with a lower risk of serious infections as compared to anti TNF agent again, recognizing that the efficacy of use you can map is pretty good, including in patients or other way to the end of refractory, similar observations as before. Very busy may not offer much of a safety advantage when it comes to Crohn's disease, particularly refractory chronic disease. Uh So overall should we choose uh safety or effectiveness in making our decisions? I would submit that almost always just be, we should be choosing an effective drug over the safer drug when it comes to Crohn's disease. In improving the overall outcome for the patient. I'm gonna skip through the slide. What this basically is trying to contextualize is patients have a baseline risk of serious infections based on certain factors. And then if you choose a risk congruent therapy, trying to balance the risk of disease and treatment complications, patients may follow different pathways says that a patient who gets put on the right therapy achieved remission, their overall risk of serious infections is going to go down. Whereas if they choose an ineffective therapy, the baseline risk of infections can be significantly modified and they make subsequently have higher risk of serious infections and treatment related complications. So summarizing the safety part, uh there are patient and disease related factors for serious infections. Several of its are non modifiable, including older ages, severe disease activity and the need for corticosteroids. And we should really thinking about, we shouldn't think about safety of a treatment approach rather than the individual agent. Both the systemic immune suppression, potential office specific agent as well as time wading effectiveness in controlling the disease are important and ensuring safety of a treatment approach. In general, I would submit we should value treatment effectiveness more than treatment safety for most patients. Uh huh. So moving on to the next part, can we personalize therapy again? Uh Not not at this stage. I I would think at this stage we're not in a position to choose the right medication for each patient based on certain characteristics. Uh This was a nice summary from Ryan Garo. Trying to look at what are the risk factors associated, predictable response to biologic therapy with the NFL for vandalism. Haven't used to kingdom ab And what you really see is, you know, severe diseases, induction, complicated genotype history of intestinal restrictions they respond to. They do not respond to any medication well. So it's not as if it's a green bar, it's a favorable response to anti TNF agents for one and read by for another. It largely holds through patients who have an early response to treatment tend to do well. Overall in this context and most for the most part, patient with priority and of expo in the absence of priority and of exposure tend to have higher rates of response to most agents. Yeah. Uh So overall there are certain factors which are predictive of response to most therapies and that's a younger basis initiation, early clinical and endoscopic response. No prior exposure to anti TNF agents. Use of immuno modulators concomitantly and generally economic disease location tends to response better. In contrast, there are subgroups of patients who don't respond to most therapies and those are patients with uncomplicated disease, funeral type petting in the disease specializing disease who have a severe disease activity at time of induction, higher inflammatory burden, extensive or deep ulcers, low trough concentrations and patients with obesity. So think about it when you're trying to personalize therapy. While we may not be in a position to specific therapies, we can certainly certain was the likelihood of responding to particular to overall any agent. This was a wonderful study from premier. Looking at a prediction tool for response to better as a man for Crohn's disease. And as we can see certain factors suggest that somebody is going to respond really well to vandalism, patients with no prior surgery, no priority NFL antagonists, no prior crystallizing disease, good baseline albumin and low bird enough information. Um that probably is going to mirror for you. So you can have an anti TNF agents. All of these are good disease prognostic markers. They may not be treatment specific prognostic markers. Mhm. Um, overall goal is to come up with a process of understanding resistance to biologic therapy right now, we're just skimming on the surface and eventually, hopefully we'll have opportunities for personalized medicine with microbiome signatures, genetic factors, immune cell in Frederick patterns interrupt hearted expression. Um none of those are reality at this point. Yeah. So how do I position therapy for chronic disease? Briefly talk about low risk premiums disease and subsequently spend more time on high risk chronic disease. So again, this was a review that I wrote with Dr sanborn for lotus Crohn's disease. Again, lotus being limited, anatomical involvement, no prior surgeries, modest impact and quality of life, no burden of symptoms and low inflammatory burden. Uh for those stations that this was incidentally detected and their otherwise asymptomatic, you may not necessarily need any pharmacological management and may just be able to monitor them closely. I simply would complete how to work up with an L. E. A. Colonoscopy at an angiography. If this is a situation where I may consider the capsule endoscopy, especially the angiography is negative and I may use biomarkers like parent were such as to monitoring and I would want to follow these patients closely. If I'm making a decision not to treat them with any agent just based on and disc optically detected my disease when other patients were otherwise asymptomatic. In contrast, if some of these patients have mild symptoms, then I may choose a big assassinated for induction therapy for William dominant disease and predniSONE herself as challenging for colon dominant disease. And if these patients achieved remission, they may not need any maintenance therapy and I would just follow them very closely. Whereas if they do not receive the mission, I would re evaluate the disease burden objectively. There's a subset of patients with symptoms are out of proportion to the burden of information and in that situation I may not escalate to a stronger therapy but rather think about an alternative cost for their symptoms. In contrast, if they have not transitioned over to high risk disease, I would treat them as I would high risk disease. Mhm. Um So what is the approach to high risk disease again, trying to factor in the risk of disease complications, treatment complications incorporating patients values and preferences, lifestyle, logistics, speed of answered costs. And here you're thinking about disease severity in the context of structural damage, inflammatory burden and impact on quality of life with this treatment related complications, things that go in at prive serious infections, prior malignancy, advanced stage and multiple comorbidities. But for patients with more severe disease, my typical first line therapies inflicting about adenoma. For most patients in choosing between inflicting about adam, a mob behind the inflammatory building more disease severe severity or perennial disease. Or somebody who's obese. I'm more likely to use infliction of as compared to ad alumina in this situation are much more likely to use combination therapy, particularly when choosing antibiotic agents. In contrast if somebody has high disease burden of more severe disease but have significant comorbidities or contraindications to TNS. I would use used as monotherapy and again, like I said, second line therapy for most of these patients. It's going to be used to kinda map I would definitely be using things in combination by this time if the inflammatory burden as I but again a subset of patients who had prior response to inflict some have been subsequently lost response had aluminum is generally my preferred agent in that same group of patients. Um In contrast if you look at patients who are more risk averse pure patients with more modern disease severity I may use vandalism at monotherapy audience. You can map as a preferred agent with higher disease severity and much more likely to use used you can imagine monotherapy and for second line try to convince those patients to go on Inflicting about Adam and one of therapy mm This is another way of trying to put things together um much more likely to favor and fixing up an adenoma mab in somebody with extensive small bowel disease, penetrating disease, periodontal disease, higher inflammatory burden and prominent extra intestinal manifestations. Uh I prefer to use used to kinda map in a patient who has severe disease but in the sense of active or recent malignancy patients of associated co moderate conditions like psoriasis or other cutaneous complications. And it is my preferred second line agent for most patients with Crohn's disease. And finally there is a map for patients with low risk genotype moderate disease activity who otherwise risk averse patients with active or recent malignancy with modern disease. Modern disease. Overall in the setting of multiple comorbidities, or for postoperative prophylaxis with that, I would stop. Published Created by Related Presenters Siddharth Singh, MD GastroenterologistAssistant Professor of MedicineUniversity of California, San Diego Siddharth Singh, MD, is a board-certified gastroenterologist who diagnoses and treats diseases of the digestive system. View full profile
