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Expert Insights on Aligning Early Advanced IBD Therapy in Real-world Practice

Q&A

Dr. Cohen: So, it looks like I have a question here for Jessica.

So, it says, Jessica, what would you do in the situation of a patient with Crohn's disease who is going to be initiating a biological or advanced therapy, moderate-to-severe Crohn's disease, but she also recently got married and is planning to start a family. How would that impact your decisions on treatments?

Dr. Allegretti: Yes, so, we know that with regards to our therapeutic landscape, the biologics, which are monoclonal antibodies, are safe in pregnancy and can be used. The small molecules, which include the JAK inhibitors and the S1P receptor modulators, should not be used in pregnancy or in patients who are imminently going to get pregnant. That being said, I would have a conversation with her about what her timeline is, what her family planning status is.

If I really thought that one of the small molecules was the best option for her and I needed to get her into remission, I would not withhold that therapy just because she is a woman of childbearing potential. But if she says to me, the second you get me better and the second I feel better, I want to start trying to have children, then I absolutely would take that into consideration because then you would have to potentially switch therapies. These are conversations that I have early and often with my patients.

I also counsel my patients early, even before they are thinking about having children, to remind them, do not stop your therapies, talk to me. We want to assess you before you start trying to get pregnant to confirm that you are in remission because we know that patients who get pregnant in remission are more likely to stay in remission and do better.

Big picture, our biologics are safe. They can be continued in pregnancy and should be, and patients can breastfeed on these therapies. The small molecules, though, can be stopped basically right up until the time they want to start trying. Both of them need about a week washout and then patients can start trying to conceive if that is what they want to do.

Dr. Cohen: And is there still a recommendation that the babies born to mothers who are on biologics, or small molecules, say biologics, avoid the rotavirus vaccine?

Dr. Allegretti: Not anymore. So, there is now data, that these babies do fine. And so there is no need to withhold the rotavirus vaccine, which happens in the first six months of life, which is an oral live vaccine. It is the only live vaccine that babies get within that first year. And so to our moms on any of our –

Dr. Cohen: In the United States?

Dr. Allegretti: In the United States, excuse me. There is no need to withhold that, so you do not have to counsel your patients on that anymore.

Dr. Cohen: But you do not give the BCG vaccine if you are to these babies?

Dr. Allegretti: Yes, if you are outside of the U.S.

Dr. Cohen: Bad things can happen. So, Jordan, we have a question here.

A patient I saw recently has left-sided ulcerative colitis, pretty inflamed. I did a colonoscopy and he was on mesalamine. And the pathologist, one of the biopsies came back indefinite for dysplasia. Should I be sending this patient to surgery? What should I do?

Dr. Axelrad: Yes, that is a good question. I think a couple of things. One is, was this a lesion, or was it just a random biopsy? If it is a random biopsy, now that patient needs to come back for an exam using image enhancement for a colonoscopy with either virtual or dye-spray chromoendoscopy. Perhaps preferably dye, depending on the study you look at. Or sent to a gastroenterologist with experience doing that.

If it is a polyp that you completely removed that had indefinite, that is great. Now you have to ask yourself, is the patient's disease activity being adequately controlled? Is the reason there was indefinite for dysplasia because disease was very active? Or was disease totally quiescent? That will impact your next treatment moves as far as therapies are concerned.

Dr. Cohen: So, this patient is on mesalamine, so you would optimize their therapy with an effective, for moderate-to-severe ulcerative colitis, and bring them back in six months, maybe re-biopsy them using narrowband imaging or chromoendoscopy.

Dr. Allegretti: Yes.

Dr. Cohen: Right? Exactly. Okay. So, Jessica, the patient here has been on an anti-TNF therapy, but now they are getting psoriasis on their scalp, behind their ears, and the umbilicus. The dermatologist has suggested that I just lower the dose of the anti-TNFs. What are the options?

Dr. Allegretti: Yes, so, this certainly does happen, this sort of paradoxical psoriasis that happens with anti-TNF therapy, even though anti-TNF therapy is also a treatment for psoriasis. So, it can, this paradoxical relationship can happen.

I work very closely with my dermatologist. Depending on how severe the psoriasis is, we often try to manage with topicals if we can, especially if the patient's doing very well on their anti‑TNF therapy. If, however, the psoriasis is really becoming a quality of life issue and really quite bothersome, which certainly can happen, the great news is that we have therapies that will treat both, and so this is a great opportunity to move to an IL-23. Any of them would be appropriate.

They all work for psoriasis as well, and so working closely with my dermatology colleagues will sort of discuss which one we think is best, depending on what is going on with the patient, but this may be an opportunity to switch to an IL-23, and then you can manage both issues concurrently.

Dr. Cohen: Okay. So, switch and manage them, especially if they are very severe.

Dr. Allegretti: Unfortunately, usually these patients, their IBD is quiescent, you know, when this happens. If their IBD is not, then, you know, even easier to switch. It is sort of sometimes heartbreaking when you have to leave a drug that they are doing well on otherwise.

Dr. Cohen: Okay. Jordan, the patient is on an anti-TNF and has developed suggestions of possible demyelinating condition. They called a neurologist who said that they do not have MS. They are coming due for their next infliximab infusion. What should I do?

Dr. Axelrad: Yes. So, this is a rare complication that can occur in patients on anti-TNF agents or sorts of demyelinating conditions that could be MS-like. So, that would make using anti-TNF relatively contraindicated. So, you would definitely have to move away from that as an option and use another therapy.

I think for that, that is an easy one, but quite rare. And usually I am leaning on my neurology specialist to tell me whether that is actually the case, right? So, patients may have symptoms that they think are MS. And, of course, a new diagnosis of MS needs to be differentiated from a complication that is demyelination related to anti-TNF therapy. You definitely need neurology colleagues to help you with that.

Dr. Cohen: Okay. So, you do not go back to a TNF. Luckily, we have more options now.

Dr. Axelrad: Yes.

Dr. Cohen: Okay. So, here is a question for Jessica. Jessica, my patient with Crohn's is on adalimumab, and whenever I check anti-drug antibodies and drug levels, the drug levels are good, but they have some anti-drug antibodies. Should I switch therapy? They are doing well.

Dr. Allegretti: So, no, right? I think, again, the key point here is that you can have antibodies that are neutralizing and non-neutralizing. Our assays are much more sensitive these days, so often we will pick up these low levels of antibodies.

I think the key point here is the patient is doing well, and they have drug level. So, where to be concerned is when you have no drug level and high antibody titers, because that means you are essentially negating drug. You are not getting any benefit from that drug, and that would be time to move on, even if the patient was doing well, right?

Because it is sort of inevitable that they are going to have a collapse at some point. But if the patient does have adequate drug levels, or even if they have got low drug levels, that is maybe an opportunity to optimize and try to overcome those low-level antibodies. I would probably get a fecal calprotectin at that point, too, just to confirm that the patient is actually doing well, even if they are saying that they are clinically fine, just to confirm that.

But if the patient does have an adequate level, even with low-level antibodies, I am not abandoning that drug in that moment.

Dr. Cohen: Okay. Jordan, anything to add to that?

Dr. Axelrad: No, no, I agree with that completely. I think we did not discuss, but as far as drug level checking, when you should do it, when you should not do it, that is also an open topic. My typical approach is that for sick patients, I will proactively monitor the anti-TNF drug level infliximab, obviously, primarily.

For not-so-sick patients that I am starting infliximab, I am actually not proactively monitoring the level. But, of course, for anyone, like just described, that is not doing well, that is suddenly having refractory symptoms, there you definitely want to get the drug level and antibody titer.

Amy Stewart (Capital Digestive Care): In patients with moderate to severe ulcerative colitis or Crohn's disease, how do you sequence advanced therapies, and which factors most strongly drive your first choice of first‑line biologic or small molecule?

I think the best answer here is really thinking about getting our patients on therapy. Getting our patients on a therapy that works, and getting them on a therapy that works quickly. How can we do this? Any advanced therapy is a good option over no advanced therapy. But thinking about the guidelines and patients who are naive, for example, in the AGA guidelines, we have this class of higher‑efficacy medications for those who are naive. Again, they are not listed in order, so which one do I pick?

Well we really go through the shared decision‑making model with the patient. First, I think about how sick are they. Do I need something that is going to work very quickly, or do I have a little bit more time? If I need something that is going to work very quickly, then I need a medication that works very quickly. In patients who are very sick who I need something very quickly, first‑line, I might be thinking infliximab, particularly if they are on the borderline of going into the hospital. However, if I have got more time, then really the doors are open to me, and I can choose any of those therapies that are positioned there for higher efficacy for naive patients.

Then I talk about options to the patients. I talk about could you get to our infusion center? Do you have an infusion center in your practice that your patient could get to that you can get drug to and also quickly? I am very lucky that in my practice, we have an infusion center that I can get therapy pretty quickly. Our average prior authorization is three days, and I can get new drug start within about 14 days, but that is not the case for everywhere. If it is going to be two months before you can get an IV, you might think about another option for that patient.

Then I also talk to the patient about continuing therapy. "Okay, if we do IV induction, can you continue coming to the infusion center, or do we need to think about something that has a subcutaneous option?"

In my practice in DC, many of my patients are young. They travel a lot. They work for the State Department. They are on the hill. They are all over the place, so thinking about them as people. Thinking about social determinants of health: do they have a refrigerator? Can they store their medication at home? Can they get packages if it is delivered to them? I have had patients who have had their drugs stolen by porch pirates. Thinking about all of these things, but also following the guidelines in terms of shifting me into certain medications or certain classes that are higher‑efficacy.

Another question that came up here is: are there particular patients who would not be considered candidates for subcutaneous maintenance infliximab or vedolizumab for their IBD? That is a great question.

In the clinical trial subcutaneous for both infliximab and vedolizumab was as efficacious as IV, but we also need to think about what dose they are currently on. If it is a patient who is already on therapy, remember that vedolizumab was compared every eight‑week dosing of IV versus every other week subcutaneous.

If I have a patient that is on vedolizumab every four weeks, I might be wary about transitioning them to subcutaneous because they already need dose escalation. That is very hard to do subcutaneous with an every‑other‑week pen.

Similarly, for infliximab, if I have a patient who is doing well on 5 mg/kg Q8, that is a great patient to think about switching to subcutaneous. However, in the studies, patients who are on 10 mg/kg Q4 week dosing, a large number of them, lost response within six months. Now, 80% of them were able to recapture response when their dose escalated. However, particularly with insurance, it is really hard to get these subcutaneous pens dose escalated. For patients who are on standard therapy, those are good candidates for subcutaneous maintenance.

The other consideration you might think about is, for me, we have our own infusion center. I can really keep eyes on these patients when they are coming in for infusion and make sure they are getting their therapy. If you are worried about someone who is going to set it and forget it and not take their subcutaneous, then you might think about that as well. Just thinking about it, I do not like to use the word compliance, but how can we keep our patient on therapy appropriately?

There is another question here. Will be practicing in internal med primary care. Will I be initiating therapies like this, or better refer to GI? I think it depends a little bit on your demographics. If there is no GI care for six months, then it is not unreasonable for you to know about these therapies and consider getting your patient on something. But I will say that, more realistically, probably these are best handled by GI. Not even all GI do a lot of IBD. Sometimes even in practices like mine, some of the doctors refer their IBD patients to certain physicians just because it is harder to keep up with, quite frankly, when there are so many things and so many therapies.

But I think our primary care colleagues can really help with keeping our patients off steroids and also helping to increase access to GI. If there is a six‑month wait and you have got a patient who you suspect has IBD or is flaring, how can you help get that patient to GI so that we are not in the urgent care cycle and steroid, steroid, steroids?

So how are you incorporating treat‑to‑target principles into routine practice, particularly with respect to endoscopic healing biomarkers and cross‑sectional imaging?

Thinking about treat‑to‑target principles, we have got the short‑term goals, which is where we want our patients to feel better. That depends on what your patient's symptoms are. In a patient with diarrhea or rectal bleeding, certainly you want those to reduce. However, sometimes our small bowel Crohn's disease patients, for example, just feel intermittently bloated, so it is about maybe they have more energy. Maybe those bloating episodes or obstructive episodes are decreasing.

In those patients who do not have diarrhea and bleeding, you are not going to see reductions in that. What are their symptoms, and how are we monitoring them?

After feeling better, then we want our patients to have improvement in their biomarkers. This thinking about in that first three months of induction therapy, following CRP, and then at three months checking a fecal calprotectin.

There are some patients who do not mount a CRP or a fecal calprotectin response. In those patients, if they do not have an elevated CRP or fecal calprotectin when they are flaring, a normal one is not going to help us. It is not going to tell us anything if it is always normal.

Thinking about those patients, what are their biomarkers that do correspond with their disease? Some patients might get anemic, or they might have an elevated platelet count. Understanding at baseline, what of your biomarkers tells us that your patient has active disease, and how can you follow that over time. Checking those labs and induction, fecal calprotectin at three months, and then when you see that start to come down in the intermediate targets, you move on to longer‑term targets, which are things like endoscopic healing.

In my practice, we usually repeat a scope about 6 to 12 months, more often 12 months. If they are doing well and their biomarkers are improving, we push it out to the 12‑month mark. If you are not sure if there is a response, if the biomarkers are not there, or the patient's not feeling well, or you are just not sure, then we might do it sooner, at six months.

Remember that in the guidelines, histology is not yet a recommendation. Meaning if you get endoscopic healing, hot diggity dog. I have got a dance that I call the deep remission dance that my patients get when they come back from colonoscopy. But if they feel good, if their biomarkers are normal, and endoscopically is normal, but there is a little bit of smoldering inflammation on histology alone, we are not currently changing therapy just on that histology alone. That is why I use those treat‑to‑target principles.

Now, if a patient, for example, has small bowel Crohn's disease, and really MRE or CT is the best way to evaluate that patient, we are typically repeating that about 6 to 12 months after starting therapy.

Our practice just got intestinal ultrasound, and so we are starting to use this at baseline, and then also early at 8 to 12 weeks after starting therapy to assess response. There are some data that you can see a response as early as two and four weeks with IUS as well, so using that, if it is available to you. I also completely understand that intestinal ultrasound is not widely available, so if you do not have it, you cannot use it. Let us use modes to monitor that we do have, so thinking about our calprotectin, CRPs, biomarkers, and then looking at endoscopy and imaging.

Another question here: what health maintenance recommendations do you emphasize for patients prior to initiation of advanced therapy and during therapy? Do you have a process of standardizing this in your practice?

This is a great question. We use the IBD Cornerstones Checklist most frequently is the one that we use in practice. There are several that exist to help keep track of all of health maintenance. Prior to starting therapy, you want to make sure your patient is up to date on all age‑appropriate vaccines. If it is a therapy that has a higher risk of shingles, we like them to get their first dose of Shingrix before starting that therapy.

Also, remember that if your patient is on steroids, they are not going to mount a great response to the vaccine. If your patient is on steroids, we wait until they are under prednisone 20 mg in order to vaccinate. Otherwise, it might be a wasted vaccine. 

With our biologics and advanced therapies, there are no live vaccines while on these advanced therapies. If your patient needs a live vaccine, they should not really unless they are travelling, but for many of them, you need to do the live vaccine, and the second one, if there is a second one, for example, like chickenpox, then you need to wait four weeks before starting your advanced therapy. No live vaccines while on therapy.

Otherwise, we often do not hold therapy while we are waiting for vaccines. We often get things going. The most important thing is to get patients off steroids and on a therapy that works for them. You can do vaccines while they are on their advanced therapy as long as they are not live. Thinking about that.

Also, it can be really overwhelming when starting a new therapy. In our practice, we have an NP or PA who sees all of our patients during their IV induction doses, so at each IV. We talk about all things health maintenance at the second infusion because the first one, it is overwhelming. We are talking about safety and answering questions, infusion reactions, et cetera, so it is at that second infusion when we do it in our practice. We also give the patient the IBD Cornerstones Checklist, we circle what they need to get thinking about dermatology, colon cancer screening, pap smears, et cetera. Then we also follow it. We check in at least annually on all things health maintenance. We try to do it six months when we can, but at least annually, making sure they are up to date on things.

I also like to write a really nice summary to primary care so that they can help us. Just writing in the chart, reviewing the IBD Cornerstones Checklist is not helpful because our primary care colleagues might not know what that is or what our patient needs, so I spell out specific things. I say: one, should have an annual dermatology visit. Two, do an annual cervical pap smear if they are on infliximab or immunomodulators, for example. Three, hep B immune, UpToDate does not need it. Four, consider Prevnar. I really make it very clear in my notes so that patients and also primary care know what we need, so that they can help us.

Another question there. How long do you keep the steroid?

Not more than three months. As little as possible. If you get a good robust response, for example, on prednisone 40 mg, I would keep them on that 40‑milligram dose for a week or two and then start to taper. I typically go by 10 milligrams until 20. I go from 40 to 30 to 20 mg and then 5 milligrams a week after that.

If a patient is very sick, they might need longer, but in general, we want them off as quickly as possible. Now, it also depends on what therapy you are starting. You do not want to taper them off the steroid before you have started their advanced therapy because their symptoms are going to come back, and they are not going to have anything to keep them there.

Really thinking about if you are starting a steroid, also starting advanced therapy at the same time, and thinking about the time of onset for that advanced therapy. If in clinical trials for a drug, it took about four weeks for about half of patients to get a response, I am keeping them on that steroid for about 20 to 40 mg dose for the first four weeks before I taper further, because I know they need time for that advanced therapy to get on board. Thinking about can we taper quickly to 20 and then maybe a little bit slower, but how can we get patients off quickly and safely as possible with tapers?

And for patients with complex disease features like perianal disease, extra‑intestinal manifestations, steroid dependence, prior biologic exposure, what are some of the most important evidence‑based strategies for optimizing outcomes?

It is really thinking about your individual patient. For a patient who has extraintestinal manifestations, we want to think about is this an extraintestinal manifestation that parallels disease activity or is separate from disease activity. What do I mean by that? Peripheral arthropathies, for example, joint pains in the hands, usually parallel gut activity, so you do not need a drug specifically that is going to treat joint pain. If you heal the gut, those extraintestinal manifestations will probably go away.

But if there is axial arthropathy, for example, that does not parallel disease activity. You can have a completely healed gut and still have axial arthropathy. You might think about a therapy that has a mechanism on joints as well, maybe that is an anti‑TNF, or thinking about a JAK or IL‑23s. When we think about extraintestinal manifestations, we want to know, does it parallel disease activity, does it not? Is one of our drugs also going to treat it? In which case, we could do two birds with one stone. For example, someone with axial arthropathy or uveitis, that is not someone I probably would choose vedolizumab in as a first line because vedolizumab is gut selective and it is not going to treat uveitis or those axial arthropathies, so thinking about that, when we think about positioning.

Perianal disease is a beast of its own, and there are some guideline recommendations for perianal disease. However, we got to go strongly with perianal disease. I think often quality of life with perianal disease is underestimated for patients.

Those who have steroid dependence. We also get them in with endocrine when we are thinking about tapering so that we can taper them safely, but also, are we really optimizing their underlying therapy? Why is it that they are steroid‑dependent? What inflammation are we not treating that only the steroid is treating?

Really thinking about our patients as whole patients using our guidelines as guides. I like to say guidelines are guides; they are not hard, fast rules. Sometimes our patients do not neatly fit into them. Using resources that you have, IBD is a team sport, so phoning a friend, getting another opinion from a colleague, if you have a physician champion in your practice, if you do not, is there another APP in the country that you could reach out to and ask some questions? What resources do you have? You are doing extra clinical education like this, so I know you want to take good care of your patients. Really thinking about all of the resources that are available to you for these really complex situations and, when needed, referring your patient to an IBD center for another opinion. Sometimes it really takes someone who is only doing IBD all day, every day, and really has this multidisciplinary team to get the best care for our patients.

When treatment targets are not fully achieved, how do you distinguish cause?

So one, if there is new diarrhea, we have got to rule out infection, we have to rule out Clostridioides difficile, especially in our UC patients, but also using all of our biomarkers. Is this inflammatory or is it not? If it is inflammatory, is it a medication that we need to check a level on and make sure that we have appropriate drug on board, or is it not? If it is inflammatory, can we dose‑optimize, or do we need to think about did this patient not respond to this class of therapy, and do we need to think about another therapy option in them?