Dr. Kinnucan: I think this is a really good segue into this next, which is really about putting the patient at the center. We have to consider that patient, their disease, and then where are we going? We know that this particular example that we just went through, a patient with active symptoms obviously impacting their quality of life. Weight loss is concerning. What is that optimal disease control look like?

Of course, symptom control is there. It is a priority not only for the patient. It is a priority for us. That maybe means depending on what their baseline symptoms are, no bleeding or rectal bleeding, restoring their bowel frequency and remembering that everyone has a different baseline in terms of what their bowel frequency is, the absence of bowel urgency, which we know is actually one of the strongest predictors for low quality of life scores is those patients, even if they have no inflammation, the presence of bowel urgency has significant impact on quality of life.

The absence of fecal incontinence, the absence of abdominal pain, no fatigue. Then we have control over extraintestinal manifestations. That is the first layer. We will talk through some of the guidance that has looked beyond this. We also need to see that objective improvement.

Jordan had talked about this in the beginning about other things that we look at, but blood markers for inflammation using C-reactive protein using fecal calprotectin. Some centers or facilities use fecal lactoferrin, but most of the studies that we have looked at are looking at fecal calprotectin. The presence of mucosal healing, the absence of ulcerations in both ulcerative colitis and Crohn's disease, and ultimately doing this all without the use of corticosteroids.

One of the things that I think David Rubin does really well in different conversations is also talking about functional outcomes. We can meet these things. We can have patients with improvement symptoms and we can meet these healing. But do they have a return to normal quality of life? Are they going back to work? Do they have restoration of mental health? You have to ask about their overall mental health to be able to assess for that. That is a really important part of clinical practice.

Do they have absence of sleep disturbances? This is some of the work that I did early on when I was a fellow, is looking at the impact of inflammation on sleep quality, but also sleep quality on inflammation. We do know that poor sleep quality can increase the risk for inflammation. It is one of those modifiable things that we can help patients with.

Understanding Patient Preferences in IBD Care

We overall have to consider and understand what the preferences are for our patients. What are they hoping to achieve? It is very similar, as you can see in this slide here with the red and the blue bars depicting Crohn's disease and ulcerative colitis. I am going to lump them all together.

What are some of those top priorities? Reduced abdominal pain, rapidity of improvement in symptoms. Patients like to feel better fast. They want to feel better yesterday. Improvement in bowel urgency, again, one of those really important endpoints that only more recently started to be looked at in clinical trial programs. Dr. Marla Dubinsky has done a lot of the work in looking at the validated measure of that, because it is hard to ask patients about their bowel urgency. It is not just absence or presence, but there is actually a rating scale. Then overall improvement in fatigue.

Discussing Treatment Risks With Patients

There are some really excellent resources that are out there about discussing risk. I really was happy to see that we were highlighting one of the articles that I did with one of my residents looking at how do we communicate risk?

Patients know that they want to feel better. You have to educate them about how important it is to actually have disease modification, changing some of those important objective markers, which means do you have to know what they are started at. You need a baseline C-reactive protein, you need a baseline fecal calprotectin to be able to assess response over time. That data trend is important.

Now, it is your job to be able to communicate with them about what the risks are associated with. Most importantly, do not talk about the risks of therapy upfront. Talk about the risks, because we really have two options here. We are either going to treat inflammation or we are not going to treat inflammation. What are the risks of not treating inflammation? They have to have full understanding because they are going to make informed decisions with informed consent.

They need to know what risks they are taking by either not treating inflammation, not choosing to go on effective therapy or undertreating inflammation, choosing to maybe go on a less effective therapy. What are the risks associated with that? As long as my patients have awareness of those risks, which many of them do not, they are unaware. They have not been told by previous healthcare providers that there is risk in not treating the inflammation, not only acute risk. What is that ongoing inflammation doing to their intestines, but also systemically inflammation can be associated with many other systemic complications.

We talk about the risk of malignancy in the colon for patients with colonic disease, but there is a risk of undertreated inflammation in the small bowel and malignancy there.

Then thromboembolic events. We know that moderate to severe inflammation can be associated with the risk of clots. Certainly, we want to make sure that that patient is informed about how important it is to treat the inflammation.

Once we have convinced them that not treating the inflammation is not an option, now we need to talk about and be able to frame risks around the therapies that we are talking about. Patients like numbers. There is some great call outs here in the box. We need to be clear in our framing. Imagery is really helpful. I personally like visuals. So I often present visuals to my patients.

Dr. Corey Siegel has done a lot of work out of Dartmouth and has really great risk visualizations that are present in terms of some of the work he has done. Then you need to use very patient-specific communication. Make this about the patient, not just all patients with Crohn's disease, but things that are particularly important to that patient.

What I often like to ask upfront is what the patient is most fearful of. You gain so much insight about that particular patient and that question, because what they actually might be most fearful of is not the therapy. It is actually they are fearful that they are going to require surgery for their disease. You now have this foundation that you understand you are not going to try to sell them on a therapy. You are going to tell them what is going to be the most effective therapy to prevent the thing that they are most afraid of, which is that they are going to end up with surgery for their disease.

That really helps you versus if the patient is very fearful because their friend's brother had non-Hodgkin's lymphoma, and they heard that these therapies are associated with that. You now have this frame of reference in which you are going to now approach that conversation. That is one of the most important questions that you can ask a patient.

Shared Decision-making in IBD

Thinking about these discussions that you are going to have, the importance of shared decision-making. Patients need to be involved in the decision. They need to be involved in reviewing how effective these treatments are. They need to be involved in discussing safety considerations. They need to have discussions around the route of administration. Then, of course, we need to also consider some of the out-of-pocket costs and the impact that that may have on a particular patient.

They are making that informed decision, again, understanding what their biggest fear is in terms of initiating an effective therapy. That is where I really get away, especially in front of patients using the word advanced therapy, because that somehow seems scarier as opposed to like basic entry level therapy, you are going to be on advanced therapy. I see we are going to be starting you on effective therapy. That sets the stage even a little bit better.

The SHARE Approach: Shared Decision-making in IBD Care

This last slide that we are going to go through is looking at this great acronym that you can think about when you are in clinic. So shared decision-making, the acronym is SHARE.

Seek patients participation, again seeking their perspective. What are they most fearful of?

Help patients compare their options. Personally I put everything in a table format. We are going to talk about these potential four classes of therapies today. Here are the names. Here are the pros. Here are the potential downfalls or concerns. Here is the top two. I never commit to top one unless I am really clear that that is the best therapy for them because again, I do not have insurance sitting with us at the table. If their insurance covers B and I was really selling them on A, I am setting myself up for a little bit less success in the future.

We have to assess the patient's values and preferences after those discussions. Reach a decision with that patient in front of you. Maybe it is not that day. Give them an opportunity to think about it unless they are very clear. I feel really comfortable going forward with A, but maybe it is let us touch base. Let me give you three to five days to take a look at the information I am going to send you, and let us touch base or let me have you meet with my pharmacist if you are lucky enough to have that resource to have further conversations.

Then we have to be able to evaluate the patient's decision. We have to put a game plan in place. We are going to start drug A, and this is what the next four to eight weeks looks like. They want to understand how are we going to assess whether or not this treatment is working for them? Of course, symptom response is easy, but how are we going to can objectively assess whether or not the therapy is working baseline and then we are going to look for follow up testing. That is how I think through shared-decision making with my patients.

With that, I am going to hand you over to Jordan.

Evidence Informing Treatment Positioning

Dr. Axelrad: Of course, Jami got to talk about all the cool fun stuff of chatting with patients and understanding their preferences and coming to decisions together. I am now going to review some of the nitty-gritty about the data.

Head-to-Head Trials Used to Formulate IBD Guidelines

What I will try to just give context for is how we can use the data to inform some of our decision-making, which I think is probably the most important thing. Head-to-head trials give us the most information about how to position therapies, what to use, what therapy, when and in which sequence.

What are the head-to-head trials that have provided some of that insight into which drug should we be choosing?

In Crohn's disease, we have had three head-to-head trials that are really important:

• SEAVUE, which was an older trial looking at ustekinumab compared to adalimumab that actually demonstrated that these drugs were non-inferior, that they were similar so that you were not sacrificing potential efficacy by choosing one over the other;
• SEQUENCE, which was risankizumab, an IL-23 inhibitor compared to ustekinumab. This showed that risankizumab was superior for most of the outcomes that were studied, in particular for endoscopic response; and then,
• GALAXI, which was a similar study looking at guselkumab, another IL-23 inhibitor compared to ustekinumab, essentially demonstrating superiority across outcomes.

In review, we have IL-23 inhibitors superior to ustekinumab. We have ustekinumab being equivalent to adalimumab.

In ulcerative colitis, we have importantly the VARSITY trial. This was a head-to-head trial of vedolizumab compared to adalimumab. This is actually an older trial. It is from 2018. This actually introduced to the data providing evidence for choosing vedolizumab as a very important and effective therapy for ulcerative colitis, specifically over adalimumab. These data just give us a little idea of how to choose therapies.

2025 AGA Guidelines: Recommendations for Managing CD

Last year, the AGA came up with guidelines where they used network meta-analysis to help us sequence therapies. They cohorted therapies based on network meta-analysis into efficacy buckets. I do not particularly love this idea of efficacy buckets based on indirect comparisons between trials using network meta-analysis. My preference would be the head-to-head trials that I just talked about.

Of course, some of those data made it into this guideline, but essentially they bucketed drugs based on efficacies of indirect comparisons and network meta-analysis. What I would just say is thinking about how Jami described how to talk to patients is that all of these drugs are FDA-approved, that we have talked about in specific disease subtypes, either Crohn's or colitis. So they have demonstrated efficacy over placebo.

The important thing is they are getting patients on drug. Many of us understand that the best drug is the one that you can get for your patient sometimes. That being said, in Crohn's disease, I just want to highlight that we know there are certain drugs that have lower efficacy. I just want to point out that vedolizumab and certolizumab, which we do not use very much of anymore. I would even group ustekinumab in that category because of some of our head-to-head comparative data with IL-23s.

Most of the time when I am thinking about therapy selection in Crohn's disease, I am thinking about anti-TNF and IL-23 inhibitors. That is what this guideline underscored.

2025 ACG Guidelines: Recommendations for Managing CD

ACG, our other organization, also came out with some guidelines for managing Crohn's disease. Importantly, they described some thresholds for helping us distinguish patients who have more active disease. As Jami mentioned, when your patient is coming in and saying they are flaring, you need to confirm that.

A fecal calprotectin that is elevated specifically over 100, pretty good for distinguishing active disease. Ultrasound could be utilized if you have access to that versus other disease activity assessments with either colonoscopy or cross-sectional imaging with an MRI. They also recommend post-op monitoring for patients who require surgery. We have specific trials that looked at therapy in the post-operative setting for infliximab and vedolizumab. We have specific data generated there. Essentially all of our biologic and small molecule therapies ought to have evidence for post-op prevention in patients who require surgery.

Then diet therapy. We do not have a lot of great high-quality studies, but that dietary modifications, specifically looking at things like Mediterranean diet or specific carbohydrate diet, could be considered for patients with more mild disease as an adjunct to monitoring.

2025 ACG Guidelines: Recommendations for Managing CD

ACG also put out some guidelines about how to manage patients, additionally, from what I mentioned, which included no longer really relying on immunomodulators and methotrexate for patients not utilize low value therapies. Specifically in Crohn's disease, we are not using mesalamine. That is not something that has demonstrated efficacy in Crohn's disease despite that it is prescribed very often.

So mesalamine no real utility in Crohn's disease. Make sure you are utilizing our newer agents, specifically the ones that have demonstrated superiority and head-to-head trials like the IL-23 inhibitors. Then, of course, avoidance of corticosteroids is really important.

PROFILE: Infliximab vs Standard of Care for Patients With Newly Diagnosed and Active CD

I just want to mention as far as the management of studies, really a landmark study that looked at when we initiate therapies. This is the PROFILE study which was a randomized, controlled trial of infliximab versus standard of care for new Crohn's disease diagnoses. This was an active, controlled, randomized trial. Some patients were diagnosed with Crohn's disease as soon as two weeks prior to enrolment in this trial. Patients were randomized to either infliximab with an immunomodulator compared to the standard of care.

That standard of care was basically an oral corticosteroid, then escalation to an immunomodulator, then escalation potentially to infliximab. Then they looked at follow up. This is our classic top-down versus standard of care step-up therapy.

PROFILE: Outcomes at Wk 48

Essentially what they saw across outcomes was that the patients who got initiated as soon as they were diagnosed on effective therapy with infliximab and an immunomodulator, they did way better on essentially all of the outcomes compared to those who stepped up.

What is really interesting about this trial that I will just mention is that some longer-term data was recently presented at some of our conferences. Even for the patients who are stepped up to therapy, who eventually stepped up to infliximab, they actually still did not do as well as the folks who were initiated earlier on infliximab. That timing of initiation, in some ways more so than the therapy selection, as demonstrated in this study, had a huge impact on outcomes. That early selection of more effective therapy is really important.

LOVE-CD: Vedolizumab in Patients With Early or Late CD

We also have some data looking at vedolizumab in patients with Crohn's disease, again underscoring the notion of when to start therapy. This looked at patients who were diagnosed with Crohn's recently less than two years or more than two years ago. I would argue that a diagnosis a year and eight months is already getting long. Again, these data underscore that early initiation of vedolizumab was better than late initiation of vedolizumab in patients with Crohn's disease.

2024 AGA Guidelines: Recommendations for Managing UC

The AGA also had guidelines for ulcerative colitis. We talked about the Crohn's guidelines. What about ulcerative colitis? They did the same thing of cohorting by efficacies based on network meta-analysis. Again, I do not personally love network meta-analysis. I love head-to-head trials which we had VARSITY for ulcerative colitis.

I do not want to go too much into it for how they have looked at these therapies, but basically for patients who had prior failure of an advanced therapy, particularly anti-TNF, those are the patients that you want to be thinking of either a JAK inhibitor or potentially an IL-23 inhibitor. That is where we have the most data that these drugs are useful.

If you have failed an anti-TNF and it is time for something else, thinking about JAK inhibitors and IL-23 inhibitors potentially in ulcerative colitis is a reasonable next step based on the AGA guidance.

2025 ACG Guidelines: Recommendations for Managing UC

ACG, not to be outdone, also came out with their guidelines. They do not attempt to sequence therapies. They basically just say use advanced therapies. Make sure you are monitoring, as Jami underscored, for demonstrating who is really flaring and who is not. Importantly, reflecting on the VARSITY data, which was head-to-head of vedolizumab versus adalimumab. Consider adalimumab avoidance in patients with ulcerative colitis when you have other options, particularly vedolizumab, where we have head-to-head data, that that is a superior choice.

Again, all of the guidelines underscore the notion of treat to target, which is, of course, not just choosing therapies, but setting up your monitoring strategy and how you are going to ensure that these therapies are working for your patient. Whether that is normalization in how they are feeling, normalization or improvement in their biomarkers, and then, of course, normalization in their colonoscopy or cross-sectional imaging that those targets need to be set and you should be making adjustments in your therapies to achieve those meaningful targets. That is based on STRIDE guidelines. That is, of course, underscored in all of our AGA and ACG guidance.

I will turn it back over to Amy.

Skill Building and Feedback: Patient Case 2—Rebecca, 45-Yr-old Woman With Left-Sided UC

Amy Stewart: Perfect. Thank you so much, both of you, for going through that. Let us get into a patient case. This is Rebecca. She is a 45-year-old woman with left-sided ulcerative colitis. She has persistent urgency, rectal bleeding, nocturnal stools, so the need to have a bowel movement is waking her from sleep.

She is moving her bowels six to eight times a day, despite optimized mesalamine. She has required two prednisone tapers in the last 12 months and, not surprisingly, she becomes symptomatic when prednisone is discontinued. She is currently also on metoprolol.

A flexible sigmoidoscopy showed a Mayo endoscopic sub-score of two to three. Her fecal calprotectin is 1650. Hemoglobin is 10.8. Her heart rate is 47. She has no dysplasia now or history of dysplasia, but her past medical history, she has got a second degree AV block and prior optic neuritis. What is your overall clinical impression here of Rebecca?

I want to first start with talking about prednisone. She has been on mesalamine and she has required two prednisone tapers in the last 12 months. Is that something that you would do in your practice without making any changes?

Dr. Kinnucan: I can jump on that. Oftentimes I also think that sometimes people knee jerk reaction to prednisone too soon. Again, what I love about intestinal ultrasound, but you can still get this in the data that you are seeing here with the flexible sigmoidoscopy is fecal calprotectin tells us that there is inflammation versus not. Knowing it is not perfect, there are some patients despite inflammation that will have a normal fecal calprotectin. The numbers are pretty small in the colon.

Some of the highest that you will ever see are those patients with just proctitis. Just the number alone being elevated does not tell you where that inflammation is. Ultrasound in my practice, if this person was sitting in front of me in clinic. She has got an elevated fecal calprotectin. She is clearly having symptoms. Many of her symptoms are speaking to the location in the distal colon rectum, urgency tenesmus, nocturnal awakenings. She is not able to distend the rectum, but ultrasound would help me prove that.

Ultrasound could be normal throughout the colon, which means that I am dealing with somebody with proctitis. Maybe we need to deliver the medication that she is on right where her inflammation is.

She has got severe left-sided colitis. So this is different. Really, there is very little role of mesalamine in patients with moderate to severe disease. Really we should be looking at more effective therapies.

If you inherit this patient or she had done really well and she had achieved a level of healing on mesalamine, there are patients who surprise us. Maybe she would benefit from per rectum therapy to help her bridge over as opposed to systemic steroids. That per rectum therapy could be in the form of mesalamine. We also have budesonide foam available to us that reaches a little bit higher up and has some good efficacy, especially in patients who do not respond to mesalamine.

In a patient with this more significant disease, if she had a prednisone course on mesalamine and had recurrence, she has bought herself a ticket to effective therapy. That is where, I guess, Jordan, you can comment on this and I bet, Amy, in your practice, we never get to see these patients. I never get to see a patient who has just been on mesalamine and I have all of these treatments I can talk to them about. These are exciting patients to be able to have those conversations because you are not limited, you can really, truly start to talk about many of the therapies that are effective in them.

Dr. Axelrad: Yes, I would just add a couple of things. Jami did a great overview. Obviously this patient is coming in with symptoms. You have done the work and you know there is evidence of inflammation, right? You have done the work, the calprotectin is elevated, the patient is anemic. There is a scope that is showing active disease, moderate severe. It is a sub-score of two to three, but let us just call it a three because it is severe.

Now the patient has been requiring corticosteroids. This is someone who is obviously poorly controlled. You have to do something.

Optimized mesalamine. We can talk about what that means, but regardless, this is someone who needs better therapy than what we are doing. Important that they know it as far as starting to think about what therapies you want to offer this patient. They mention that the patient is on a beta blocker and has a history of second degree AV block and prior optic neuritis. I would not get into the merits of AV block and beta blockade, but this is someone that maybe you would want to avoid S1P receptor modulators, where they have been associated with bradycardia. You cannot use that in patients with heart block and you cannot use it in patients that have certain conditions of the eye, including optic neuritis and macular degeneration.

I just want to point that out that essentially that class is going to be excluded because of some of these issues. As Jami mentioned, everything else is on the table, essentially. Then it is about choosing wisely based on guidelines of what could be a more effective therapy here. Maybe thinking about VARSITY, where vedolizumab was superior to adalimumab, or the IL-23s, which have shown their superior to ustekinumab. Then it is more about choosing wisely and then based on what is important to the patient.

Amy Stewart: Those are all really good points. The fun part about being in a community practice is not only do I get to newly diagnosed patients, but I also get to give them their first advanced therapy, right? I see patients like this in my clinic all the time. When I am teaching about prednisone, I like to call steroids a necessary evil. Sometimes we need them in short little bursts, right?

This patient in particular has required two prednisone tapers. If you do not change the underlying therapy, then these steroids are a bridge to nowhere. It is not surprising that symptoms come back because the underlying therapy is not controlling disease.

Posttest 2

Moving on to a posttest question. This is a 52-year-old woman with severe ulcerative colitis on infliximab five mgs per kg every four weeks. She is having eight bloody stools a day. Nocturnal symptoms, urgency and Mayo 3 pancolitis or severe disease on colonoscopy. Her infliximab drug level is high, consistent with a secondary loss of response. She has coronary artery disease with prior MI, former tobacco use and prior herpes zoster. She does not want to continue with an infusion therapy. Which is the next best step?

1. Start upadacitinib since it is an oral option;
2. Avoid advanced therapies due to the patient's cardiovascular comorbidities;
3. Continue infliximab; or
4. Start guselkumab since it offers subcutaneous induction.

In pre-test, 31% of participants chose A and 50% chose D. Moving on to post-test, 72% of patients chose D as guselkumab.

Posttest 2: Rationale

We will talk about some rationale. It is the only IL-23 inhibitor currently approved for both IV and subcu induction, which aligns with our patients wish to avoid IV therapies. In prior advanced therapy-exposed UC, JAK inhibitors may be highly effective, but this patient has several features that might require careful individualized risk assessment. Note that they are not necessarily contraindications, but we just really need to think about carefully in this particular patient.

She is had an MI. She has got cardiovascular risk factors, smoking history and prior zoster. The AGA’s living UC guidelines support advanced therapy use in moderate to severe UC and stratify options by efficacy and prior exposure, but patient comorbidities and safety profile should guide the final positioning.

Posttest 3

One more posttest question here before we move into our last didactic section. This is a 28-year-old woman who was diagnosed with Crohn's disease eight months ago after presenting with diarrhea, abdominal pain and weight loss. Ileal colonoscopy shows moderate ileocolonic Crohn's disease with ulcerations. Fecal calprotectin is elevated 1850 and CRP is elevated. She has required one prednisone taper. She is currently on azathioprine but continues to have symptoms. She also has a history of recurrent respiratory infections. Which treatment would you recommend?

1. Stop azathioprine and start upadacitinib;
2. Continue azathioprine and add mesalamine;
3. Stop azathioprine and start vedolizumab; or
4. Continue azathioprine with prednisone tapers as needed.

In pre-test, 22% of participants chose A and 40% chose C. In post-test, 24% of participants chose A and 56% chose C.

Posttest 3: Rationale

Let us get into some rationale here. The most appropriate answer here is C. This patient has early bio-naive moderate Crohn's disease with objective inflammation and inadequate response to conventional therapy. Here we are looking at that LOVE-CD phase IV, open-label cohort study. Let me ask you this, Dr. Axelrad and Dr. Kinnucan. Would it be wrong to choose upadacitinib in this patient?

Dr. Axelrad: Yes. In this setting, it is not that it is wrong. We should also mention there has been an FDA label change on upadacitinib. It used to say you cannot use this drug until patients have specifically been exposed to anti-TNF therapies. The label change now from the FDA just says you can use it when using an alternative therapy is “Clinically inadvisable.” I would say this is a patient here who has never been on an advanced therapy before. It is a new-ish diagnosis eight months ago.

Actually, you could choose anything, but I probably think about holding on to a JAK inhibitor in this patient, particularly if they have really never been on any other effective biologic or small molecule before. I would probably hold on to upadacitinib in my back pocket and try something else that may be a little bit safer and just as if not more effective.

Vedolizumab, based on the LOVE trial, is a reasonable choice. All of the IL-23s would be a very reasonable choice. Again, those are not oral, but certainly a lot of data and then maybe a little bit safer. You could hold on to upadacitinib if you needed it in your back pocket.

Amy Stewart: Perfect. Thank you so much. Go ahead, Dr. Kinnucan.

Dr. Kinnucan: Yes. I would have to agree. Also in this particular situation, you are really setting it up with ileal colonic disease. Maybe this is a colonic patient. If this patient was an isolated ileal disease, I think that, while LOVE-CD did not look at that in particular, I do think that some of our other studies in the GEMINI program, as well as some other studies, really showed superior efficacy of this particular therapy in non-isolated ileal disease.

A severe patient with ileal disease has had a diagnosis for greater than two years, I am certainly not thinking vedolizumab for that, but I do think that the LOVE-CD study was very helpful to inform which patient with Crohn's would you be thinking about this particular therapy in? This is a nice example, but if you had said isolated ileal disease, I would have said C would have been the wrong answer.