As many of you probably remember, mast cells used to be like the it thing for IC years ago. And recently that's sort of been called into question as to whether they're necessary for the diagnosis, not necessary, et cetera. So Professor Walker is going to clear all that up for us, and then maybe we'll have a chance to talk about possibly other biomarkers for interstitial cystitis. So Steve, take it away.
Stephen Walker: Great, thank you. And clear it all up might be an overstatement, but I will talk about our views on mast cells and related biomarkers.
So I started in IC research maybe 10 or 12 years ago. My background's molecular biology and genetics, so I don't come from this from a histology background or a histopathology background. Been fortunate to now have a histopathologist in the lab, so that's why we're starting to get some of this histopathologic information out there.
What I'll talk about real briefly today is a little bit about what IC/BPS is for those of you that are not really familiar with it. The focus of the work that I've done for the last 10 to 12 years is looking at patient stratification because it became clear early in the process of me being involved in this with the clinical folks is that the features of IC/BPS make it difficult to diagnose and treat. So we'll talk a little bit about that.
I'll give you some impressions from histologic data that we got early on. This mast cell revisited the paper that we just published recently and then some recommendations regarding how to use histopathology and that kind of information in a diagnosis and treatment plan.
So just a quick background. IC/BPS is, unfortunately, call it a diagnosis of exclusion. It's a chronic pain disorder. It affects maybe 5% of the US population.
The interesting thing about this and other complex conditions is it's highly heterogeneous, meaning there's a chief complaint, but there are often and almost always co-occurring or comorbid medical conditions that impact the main phenotype that you're looking at. In this case IC/BPS.
The AUA guidelines says you should have pain for greater than six weeks duration, pelvic pain of often unspecified origin, but may be attributed to the bladder. And again, it's a diagnosis of exclusion, so you rule out things like UTI to arrive at this diagnosis. So there are some heterogeneity in every aspect of this.
So when I get started on this thinking about IC/BPS, what became clear is clinical trials were showing low efficacy and treatments for patients, although there's a hierarchical treatment scheme that patients can go through from the least intrusive all the way to surgery, but none of the treatments are very effective for the majority of patients. And so why is that?
Well, when we looked at it, one of the things in terms of clinical trials was patients were being herded in as a group. So we pick 100 IC/BPS patients, and we test a therapeutic on them, and then we come back with a efficacy of 15 to 25% or less.
And the reason for that may be that the treatment is absolutely terrific for a subset of IC patients, but if you take 100 patients from this heterogeneous mix and then apply a therapeutic that targets one or another of the potential etiologic reasons for IC, it's not surprising that maybe the majority will not respond. So anyway, that's the framework from which we started.
Because of where I am it's tertiary referral center for IC patients, we see thousands of patients a year. And one of the standard therapeutics that Dr. Evans, who's the primary IC doc here, uses is hydrodistention for therapy, one of the therapies. And because of that, every patient that we enrolled in this now 10-year biobank and clinical database exceeds 750 patients, and every one of them has had a hydrodistention, which means we've collected a clinically indicated biopsy at the time of hydrodistention. And we also have an anesthetic bladder capacity, the actual size of the bladder, how much you can extend it to, which, again, is different from functional capacity.
But the interesting thing about that is, and it hadn't been done before in this way because we have, again, 700 patients and a lot of them longitudinal for which we actually have a measure of how big is their bladder. And so the average capacity of an adult bladder is in the range of 800 to 1,000 cc's. And we have patients that are all the way up to 1,400 cc's down to 100.
So if you think about that for a minute, if your normal capacity is 800 cc's and your actual physical bladder capacity at this point you're being seen in the clinic is 200, that's a fourfold decrease in what the size should be. And so lots of questions. How do you get to that point? Does everybody get to that point? Is this a progression, or are there a subset of patients that actually get to this point, and can you track what sorts of triggers there are that lead some subset of patients down this sort of end-stage bladder phenotype?
Anyway, so that's where we focused a lot of our attention. And for years now we've been trying to characterize patients on a background of their anesthetic bladder capacity. And when we looked at histology in these patients, we published a paper years ago that looked at a series of patients with various size bladder capacities and other characteristics. And one of the things that came out of that was mast cells are not a very good marker. The clinicians I work with say when we get the Path reports back, they rule out cancer, but beyond that, or if there's [inaudible 00:06:50] inflammation, you can see that when you do the cystoscopy because Hunner lesion is a feature here, and it's prominent.
So for the rest of the patients, the Path reports were not very useful. And so that's what took us down this path. We published that a while back.
The role of mast cells then and now is highly debated a topic. There's no doubt if there's a high number of mast cells that has an implication for the disease and disease trajectory, but what that number is and how this is measured, it's the problem.
So what we did from the initial paper, now that we have a histopathologist in the lab, we looked at 461 diagnostic pathology reports that were recruited since 2011 and asked the question, how are their mast cells measured, and what did that tell you? And what we find is the pathologists in the clinical labs use a number of different stains for mast cell evaluation, counting, and then they also use different ways to count. So some will say there are a few, there are a whole bunch, or there are a lot. Others will do mast cell counts per high-power field and so forth.
So at the end of the day, this information is not standardized in any real way, and it makes it really difficult for a clinician to make sense of it. And so what we recommended is to implement more information into the diagnostic report and specifically including mast cells.
If the mast cells are increased, well, you want to determine if they're increased. And so we would like to advocate for a more standardized way to stain for mast cells and to actually count for mast cells.
So this is just an example of a report. And I'll tell you in the original series we did, we had 40 pathology reports. They were generated by 25 different pathologists, and the information was all over the place in terms of what the findings were. And especially mast cells was one of those things where since it wasn't standardized, it's hard to make any sense of if it has a moderate amount of mast cells, what does that mean? Things like that.
So the take-home message is we believe and we're advocating for and we're continuing to work on this for improved standardization regarding this histologic analysis and reporting when you take biopsies from patients with IC/BPS so that the interpretation can actually be more meaningful.
Alan Wein: So do all the patients that come in get hydrodistention and biopsy? Is that the first step in Dr. Evans' evaluation or one of the first steps?
Stephen Walker: That's actually a great question. The answer is a resolute no. This is a third-line therapy, and it's recommended for people who fail first and second-line therapies like modification stuff. So we see thousands of patients. So in 10 years, we have a cohort of 700 that have gotten one or more hydrodistentions.
Alan Wein: Gotcha.
Stephen Walker: The vast majority do not. Yeah.
Alan Wein: So if someone does have what the pathologists call a high mast cell count, however they quantitate it, does that indicate that a specific type of treatment would be more advantageous than any other?
Stephen Walker: Not specifically. It would be an indication of more activity at the bladder mucosa and inflammation. And so you would probably be thinking along the lines of instillation or other therapies to mitigate an inflammatory response. But our phenotyping has actually demonstrated that there are at least a couple of phenotypes of IC patients we believe, and the end-stage bladder or the progressive patients probably represent a pretty small percentage.
Now that's not to discount mast cells in the rest of the patients, but I would posit that between 80 and 85% of patients are what the MAPP would call widespread pain or bladder pain syndrome patients and maybe the other 15 to 20% are actually the IC patients.
And one other thing you might find interesting. Historically the IC patients, if you're going to classify it that way, and I think the Europeans do already, they think of IC as Hunner lesion IC/BPS. So if you have Hunner lesion, that's a positive diagnosis for IC. And so you would expect, those patients usually have more severe symptoms, they have lower number of co-occurring conditions, they're typically older, and they don't respond to therapies that most of the rest of the patient population do. So if there is truly a progressive phenotype, the Hunner lesion patient would probably fit into that description nicely.
Alan Wein: Are there any promising biomarkers for IC/BPS?
Stephen Walker: That's a great question. And I started in this looking for biomarkers. Best case scenario would be a peripheral biomarker, so it's non-invasive. You can track progression, you can track treatment, and all that. And so people looking in urine naturally, we've looked at for biomarkers in the bladder mucosa, and we actually have found gene expression profiles to track with each of these phenotypes that I was describing, not as cleanly as you might like, but pretty cleanly. So I can do gene expression profiling, for example, and segregate bladder-centric from non-bladder-centric based on the way I described it.
We have peripheral blood from these patients, and I'd love to see if there's a correlation between markers in peripheral blood with IC phenotype, but there's not much history of that type of work. And blood-based biomarkers are a little bit trickier because often the markers that you find don't directly seem to be implicated in the disease process, but they're present. And so if you can find a definitive marker, it really doesn't matter why it's there, but if it has a high sensitivity and specificity, that'd be great.
Alan Wein: Listen, thank you so much because I think now people at least understand that, hey, it's an interesting thing to look at, but if work is still ongoing, it's not something that the average clinician should put into their repertoire to make the diagnosis.
Stephen Walker: Absolutely. Yeah.
Alan Wein: But listen, thank you so much. Appreciate it. Say hello to Bob Evans and everyone.
Stephen Walker: I sure will. Yeah. Thank you so much.