IBD Drive Time: Dana Lukin, MD, on Ulcerative Proctitis

Drs Raymond Cross and Dana Lukin review isolated ulcerative proctitis, including risk factors, diagnosis, mimics, and cancer surveillance.

Raymond Cross, MD, is Medical Director, The Center for Inflammatory Bowel and Colorectal Diseases​, The Melissa L. Posner Institute for Digestive Health and Liver Disease at Mercy Medical Center​, in Baltimore, Maryland​. Dana Lukin, MD, is the Clinical Director of the Jill Roberts Center for IBD and Associate Professor at Weill Cornell Medical Center in New York City, New York.

Welcome everyone to IBD Drive Time, which is the official podcast of the AIBD Network. Delighted to have my friend and colleague Dana Lukin from Cornell here today to talk about ulcerative proctitis. Dana, welcome to IBD Drive Time.

Dr Lukin:

Thank you so much for having me, Ray. It's an honor to be your guest today and hope we have a great conversation.

Dr Cross:

I'm sure we will. So let's just start out with some numbers. So approximately what percentage of patients have isolated ulcerative proctitis?

Dr Lukin:

So it's important to understand that when we talk about the extent of proctitis, that we're talking about not only endoscopic involvement, but also histologic first and foremost. But most studies have cited somewhere between 20 and 55% of patients that have ulcerative proctitis. If you look at the largest systematic review, they found around 29% or 30% in a large number of population-based studies. So I usually cite around a third of patients at presentation.

Dr Cross:

And so this is less so with Crohn's disease. Usually location in Crohn's is pretty stable, but in ulcerative colitis, we know that patients can extend and they can regress. So of those patients who start out as ulcerative proctitis, what percent of them will extend to develop left-sided disease or more extensive or pancolitis?

Dr Lukin:

So it's actually quite a bit more than you would think. If you look at the ACG guideline, they cite about 46% of patients that present with proctitis will eventually have more extensive disease on follow-up. This probably happens in stages. About 10 to 20% are cited within the first 5 years and then up to about 30% after 10 years. So I think that there is a good amount of early extension, but some of this is happening even further out.

Dr Cross:

So I like keeping things simple. So if we want to keep it simple, we could say about a third of patients are going to have ulcerative proctitis and about a third are going to extend. That's not an unreasonable rule there.

Dr Lukin:

Yep, that's great rule of thumb.

Dr Cross:

Now I don't know, my guess is at Cornell, you don't see a lot of early onset disease. I'm in sort of a mixed practice where I do get some direct referrals from primary care, but also referral. So we don't see a lot of newly diagnosed ulcerative proctitis, but when you see a newly diagnosed patient, are you thinking about any other mimics things that maybe are mistaken for ulcerative proctitis?

Dr Lukin:

Yeah, I think we do see this quite frequently and maybe you're right, being in a referral center, we see things that are sent to us with a presumption of ulcerative proctitis that equally important to understand when it's not. I'd say probably the biggest basket of mimics that we see are infectious. And so one big one is lymphogranuloma venereum, which is most commonly with a chlamydial infection and it can present almost identically. Obviously, it's very important to take a social history for patients to understand if they're at risk. And we do rectal swabs that you can send from the office to test for this and can actually save the patient quite a bit of difficulty in treatment. Other infections, herpes simplex, CMV, can present this way in at risk patients. There are reports even of mpox, which is very interesting. Outside of infections, I think it's also important to understand what the patient has been through.

For patients with prior history of cancer with radiation, particularly prostate cancer, radiation proctopathy is fairly common. There are a number of others in older patients, including solitary rectal ulcer syndrome, which can present with rectal bleeding and rectal pain. There are a whole bunch of things that don't fit that bucket, obviously with our medication history—NSAIDs, NSAID, NSAIDs—but we're seeing a lot of immune checkpoint inhibitor colitis and that can present with proctitis. For patients who might have other rheumatologic and systemic manifestations, we always want to think about or mimics Bechet's vasculitis, common variable immunodeficiency. And again, if this patient has other risks like bone marrow transplant, GVHD can present as ulcerative proctitis or as proctitis.

Dr Cross:

Yeah. And I think I wrote up a case report with Cindy Wynn and Kofi Clarke from Penn State. There was an IBD live presentation where it was syphilitic proctitis that was mimicking Crohn's. And I probably should get in a better habit of just when I do my Hep B and C serologies and QuantiFERON Gold, getting an RPR; wouldn't be unreasonable to do that. But I think the most important thing there is, and these are going to be more younger and middle-aged patients, is asking the sexual history questions of high-risk behavior that would put patients at risk in thinking about this.

You and I have been doing this about the same amount of time, I don't think I've ever seen a good explanation for this. You take a patient who has extensive colitis, put them on any treatment, treatment A, and you then rescope them and you see that the transverse colon is healed, the descending colon is healed, and the rectum is still inflamed, but everything proximal healed. Do we know why that happens? And it's pretty consistent that ulcerative colitis, you heal from the top down.

Dr Lukin:

Yeah, it's a phenomenon I think everyone talks about, but we know, in actuality, very little about. People have speculated a number of ideas. And I think the first is that as we talked about the proximal extension, most ulcerative colitis is starting in the rectum. And so you can think of this as maybe the epicenter of the inflammatory process and that it's sort of healing where it's most inflamed and where it's been inflamed the longest it's going to take longer for that. Very interestingly, one formal way that this has been looked at is in a few ulcerative colitis trials with TNF inhibitors. So post-hoc analysis of hibiscus and the GARDENIA where they use infliximab and adalimumab, they actually showed that endoscopic improvement in the left side, the descending colon was significantly higher than in the rectum. And even if you look out to a year, it's taking longer for those patients rectums to heal.

So it's a very interesting phenomenon that's probably real. People have thrown out ideas that there's these regional immune differences where there's gradual progression of innate immune cells from cecum to the distal colon, and this might increase TH17 cytokine levels in the distal colon. Other people have thought that maybe there's stool present in the rectum that is irritating, either leading to mucosal barrier defects or directly irritating the rectal mucosa. So I think it's unknown and very interesting phenomenon.

Dr Cross:

I wonder if in some of the clinical trials where patients have had left-sided or extensive, the problem with the Mayo score is if you had a Mayo score of 3 in the entire colon and you heal everywhere, but the rectum, your Mayo score is still 3. But I wonder, and those patients have had serial scopes if they see over time, whether you do get progressive healing in the rectum just with continuing the therapy. Very interesting. I don't know if they collect data in a way that they could really answer that question, but it would be interesting.

Dr Lukin:

Yeah, I think that some of the newer endoscopic tools that are available may be able to quantify this better. And I think it's interesting because I think it's meaningful when you have healing in most of the colon, even if there is some proctitis left, and I have been burned changing that very effective therapy for a patient with 5 centimeters of Mayo 3 and then you don't find anything quite as effective as that therapy. So I think we need to learn and study more about this.

Dr Cross:

How do these patients with UP differ prognostically from patients with more extensive colitis?

Dr Lukin:

Yeah, so if you look at population-based studies, there's a significantly lower association with need for colectomy with colorectal cancer. I think those are probably the major things. And so what do patients worry about when they have ulcerative colitis is, am I going to need surgery? And so I think that's one major distinction. In general, I think that there's less use of systemic therapies and maybe because these patients are most commonly excluded from the clinical trials. It's interesting because when we look at our guidelines, which are a treat to target of endoscopic healing, one of the major reasons we do this is to decrease risk of things like colectomy and colorectal cancer. And so it's less clear that these guidelines apply to ulcerative proctitis. So overall in I think the 20-year risk of colectomy for ulcerative proctitis is around 13% as compared to other types and no significant differences in several population-based cohorts in terms of colorectal cancer.

Dr Cross:

And I think that what really bugs me is it's not uncommon to get a referral from the community where a patient's really struggling with horrible proctitis and they've got topical therapies dripping out of them and they've never been advanced because it's just proctitis. Well, Dana and I will tell you that patients that have really horrible proctitis are absolutely miserable and the guidelines are very clear that when conventional therapy fails, you're considered to have moderate to severe disease and it doesn't mention disease extent as being something that precludes you from going to an advanced therapy. So when you've done a good trial, whether it's a good trial of topical therapy, one with or without oral therapy, and that patient's still symptomatic, that patient qualifies for an advanced therapy just like anyone else. So you shouldn't wait just because it's just proctitis. And as Dana pointed out, a third of those patients are going to extend over time anyway and be more extensive.

So I think you agree with that.

Dr Lukin:

Absolutely. And one thing I always wanted to bring up is that there are a ton of refractory patients and even though the majority have an excellent prognosis and maybe their symptoms aren't relating to some of these really bad adverse outcomes, as you mentioned, ulcerative proctitis affects the area which is going to cause the patient the most symptoms. Tenesmus, urgency, waking up overnight, just really morbidity that is affecting them 24-7. And so the reason we have urgency as one of the metrics in all of our studies is because it's really bothersome to patients. So absolutely, I agree with you completely. If a patient is not responding to your conventional therapies and this would apply at all levels, it could be moderate or severe pancolitis, you want to treat them the same way.

Dr Cross:

And I think the other thing that really handicaps these patients is that we look at stool frequency and we look at rectal bleeding. So these patients have rectal bleeding, that's clear. But oftentimes if you ask them how many times they're going to the bathroom, they may say 2 or 3. But then if you ask them, how many times did you sit on the toilet because you felt like you had to go or you passed just some blood and mucus like, oh, I went 12 times. Well, in practice, I count that as 12 because it's 12 trips to the toilet. But if you use a PRO2 or the Mayo score, they may be downgraded in their symptom severity, which is really inappropriate.

Dr Lukin:

Yeah. I think one way to get at that question is I say, how many urges do you have and how many movements do you have? Because many times patients are coming to you with a complaint of constipation and actually it's not constipation, it's tenesmus. They're feeling like they have to go to the bathroom, they're sitting there and straining for 30 minutes, then the bleeding gets worse. And so I think it does perpetuate itself. And so I actually do try to listen to what the patients are saying and it's really important because that may affect how I treat them. And certainly a little bit of counseling may also help the patient to understand the difference between true constipation, which may be present more frequently in ulcerative proctitis as well, because the rest of the colon is not involved and can actually function the way it's supposed to function, but also in helping them to avoid maybe reprogram how tenesmus affects them.

Okay, if it's not happening, stand up, go back and then come back later because if it's ready, you can come back.

Dr Cross:

We have a big neurogastro center at Mercy and we have really wide open axis for anorectal manometry. And I see a fair number of these patients that develop dyssynergic defecation because of that sort of maladaptive bathroom pattern of sitting on the toilet straining because you feel like you have to go. And it's exactly like you said, you need to get up. You can't keep straining. It's a false signal that you have to go, but it can be very difficult.

Before I ask Dana a few more questions, I just want to remind the listeners that we are the official podcast of the AIBD Network. We have an advance as an IBD regional course coming up July 11th and July 12th in Dallas. I will be at that course, so I hope to see you there. Also, remember that you can find us on Apple Podcast and Spotify.

Dana, what about calprotectin? So we're in a world now of treat-to-target where we're obviously still concerned about symptoms. We're trying to pair symptoms to a noninvasive test such as a serum or fecal biomarker. Ultrasound, unfortunately, in the US isn't very good for proctitis. They do do a little bit of that in Europe where they do transperineal ultrasound and of course we're doing scopes. CRPs aren't great in ulcerative colitis, particularly distal disease. How does calprotectin fare in proctitis?

Dr Lukin:

So that's a great point because it's not as well correlated. If you look at the sensitivity and specificity far lower in my clinical practice, I think I will test the calprotectin in everyone. If it's elevated at baseline, I think it is helpful because you have a grounds for comparison, but if it's not, it does not mean that they don't have active disease in a short segment. If you think of calprotectin, it's an enzyme that's made by neutrophils and extruded into the lumen. So that's happening throughout the bowel. Your bowel movement is actually forming as it transits through the intestine. By the time it gets to the rectum, it's often a formed bowel movement. So unless you're catching some material on the way out, that bowel movement may not contain a lot of calprotectin. So I think it's useful when it's elevated. Certainly it may be worth checking in the future for patients when it's not elevated at baseline because you may detect proximal extension, et cetera, but you do have to take the results with a grain of salt and listen to what the patient's telling you and also scope that patient.

Dr Cross:

And if you're checking CRPs regularly too, the other concern is if all of a sudden you see that CRP pop, that could be a sign that this patient's now has extended into the more proximal colon just like the calprotectin. So Dana, if you see someone with ulcerative proctitis with mild to moderate disease, how do you approach their treatment?

Dr Lukin:

So first we want to risk assess that patient. So what does the colonoscopy look like or flexsig look like? First of all, what is the visible extent? And we think of formal definitions of proctitis now being around 15 centimeters or less with more extensive disease proximally. We're doing biopsies not only in the visibly inflamed segment, but also the adjacent segment because I like to understand is there a microscopic disease more proximal, in which case I'm going to treat that patient more like a left-sided ulcerative colitis patient. Remember that your suppositories will have a penetration of about 5 to 10 centimeters, so that might not hit all patients with more proximal proctitis. So in general, I will start with a mesalamine suppository 1000 milligrams twice daily. Twice daily is difficult because as Ray mentioned, that these products are sometimes dissolvable and not pleasant for ambulating.

So for patients in bed, I think it's a little bit easier, but the twice daily can be used for someone who's really more active. Or in selective cases where patients really don't want to take a suppository, I think it's reasonable to try an oral mesalamine. It's got to trickle to the area of interest, but it will get there. And so I will start usually with a monotherapy and if the patient is responsive, then I think you can find the sweet spot for that patient. As I mentioned, it's unclear how much we need to treat to that target of a pure endoscopic healing. It's largely driven by how the patient is feeling. And so you might be able to get that patient on every other night suppositories or every third night. For patients that aren't responding to the monotherapy, then usually you would add the flip to that regimen.

And there are certainly a role for limited courses of rectal or more systemic steroids. There's a recent trial actually that hasn't been reported yet for hydrocortisone suppository at higher doses than are used for hemorrhoids that might have a role in some of these more acute flares. I think our budesonide foam and hydrocortisone foams have a role in the short-term management as well of these mild to moderate patients. If they're not responding to conventional therapies, then I think we step up our algorithm to more systemic options

Dr Cross:

And I agree. I think the foams for these proctitis patients could be really nice because they're so easy. They just squeeze them in. They don't have to really hold it. It's much easier. But sometimes for reasons not clear, the budesonide foams can be access to this can sometimes be a challenge depending on the insurance. For anyone with Medicare, it seems impossible to get those products to them, which is really disappointing.

So when your patient's now moderate to severe, either because the Mayo score is a 3 or because you've tried oral and topical mesalamine, maybe you've even done a couple week course of a steroid topical and they're still symptomatic, does your approach change at all compared to someone with more extensive disease or are you basically offering the same type of therapies?

Dr Lukin:

Well, I think initially it really depends on how much this is affecting that patient. We utilize a tacrolimus suppository quite a bit in our practice. I think for several weeks, 4 or 6 weeks, this can be a nice adjunct to see if that patient can actually cool down and then you can maintain them on their mesalamine suppository. So I think that that's an option. Again, if that patient is 15 to 20 centimeters, maybe we'll see if a mesalamine enema might be helpful just to get a little higher penetration, but otherwise we're thinking of our more systemic options. And these are relatively understudied; in terms of the clinical trials we saw with etrasimod, they specifically included those patients in the clinical trial program. So we have really nice data to suggest that as compared to more extensive disease, the subpopulation with proctitis actually responded quite well, not that it didn't work well in the general population, but it worked especially well in patients with ulcerative proctitis.

So that was nice that they included in the study. I don't think that the lack of inclusion in other randomized clinical trials detracts from the fact that those therapies also work. So we have mostly population-based evidence for our more advanced therapies.

Dr Cross:

Yeah, I was going to make two points. One is that I would've predicted that the ulcerative proctitis patients would not have done as well. I would've thought the ones that entered the trial just would've had that troubling sort of tenesmus and it would've been a little bit more challenging getting them into remission, but I was surprised that they actually did better. And the other thing is I think it's important to give the company credit for doing the study. So if they put the effort in, included the patients, I'm a bit of a purist. And if it's someone who's got more mild to moderate sort of inflammatory activity, more of like a Mayo 2 type disease and not severely symptomatic, I'll offer the etrasimod first because they include the patients. But if they're super sick, that's still probably an anti-TNF or JAK patient for me, even if it's limited to the rectum.

How do you survey these patients? They're considered average risk, but the guidelines have sort of changed a bit. How do you survey these patients for colorectal cancer or dysplasia?

Dr Lukin:

Yeah, so it's a little bit discomforting. I think when it's been drilled in us for years and years and years, "Oh, a patient needs a colonoscopy every 1 or 2 years because they have ulcerative colitis." This population is different. And while our data are very limited, the one study that we cite that has population level evidence is now 20, 25 years old out of Scandinavia that showed no difference in dysplasia, but that's what everyone goes by. So I think it would be great to have some more contemporary data as to what the actual neoplasia risk is. So in general, I think that the same rules apply of the 8-year colonoscopy, where you're going to do a colonoscopy 8 years after their diagnosis with both biopsies and endoscopic assessment. If they have never proximally extended beyond the rectum and they currently have no endoscopic or histologic disease, then those patients are truly average risk.

And depending on the guideline you read, it is either 5 years or average risk. And so the AGA and the ACG both say after that 8-year colonoscopy, if they remain proctitis, that average risk colorectal screening, the ECHO and BSG guidelines also say average risk colorectal cancer screening. In my own practice, I will probably survey these patients every 5 years because I can use it for both surveillance as well as disease activity assessment. But obviously for disease activity assessment, a flexsig is way simpler to do than a full colonoscopy for surveillance purposes. And so I think you should talk to the patients about it. A lot of times we don't see our patients when they're doing so well because they're not on biologics much of the time. And so it is important to make sure that the patients understand that they do need to check in every now and then and undergo some cancer surveillance.

Dr Cross:

Yeah. Jim Lewis was a guest recently and he said that he likes the 5-year scope because it gives you an idea to reassess their disease extent and determine if they've had histologic extent or macroscopic extent. So I don't think it's unreasonable to stick a scope in your UP patient every 5 years and take a look.

So what's your fun fact, Dana? Tell me something about yourself that I might not know or the listeners may not know.

Dr Lukin:

I might be maybe the one unique person in the world with this history. So I was raised on Long Island in a very small town, happened to be named Mount Sinai, which had an elementary school and a middle school when I was born. And so I went through those two schools. My sister went to a different high school, but when I was a freshman, I went to Mount Sinai High School, which just opened up. Went away for college and where did I wind up at medical school, but Mount Sinai in Manhattan. And so I did an MD and a PhD program there. Where did I do my residency? Wound up matching at Mount Sinai. So I've been at higher educational institutions for about 24 years of my first 30 now having left the Mount Sinai system, but still I have a lot of friends in both Mount Sinais.

Dr Cross:

Cool. Well, Dana, this has been wonderful. We don't talk about UP enough and you came to Maryland when I was at Maryland and did a great IBD grand rounds for us on it, so I thought it'd be timely. Thanks for doing this and hope to have you back on IBD drive time soon. All right,

Dr Lukin:

It was a lot of fun. Thanks for having me.